Novel compound having skin-whitening, anti-oxidizing and ppar activities and medical use thereof

ABSTRACT

Provided are a novel compound having skin-whitening, anti-oxidizing and PPAR activities and a medical use thereof, and the compound has skin-whitening activities for the suppression of tyrosinase, and accordingly, is useful for use in skin-whitening pharmaceutical composition or cosmetic products; has anti-oxidant activities, and accordingly, is useful for the prevention and treatment of skin-aging; and has PPAR activities, and in particular, PPARα and PPARγ activities, and accordingly, is useful for use in pharmaceutical compositions or health foods which are effective for the prevention and treatment of obesity, metabolic disease, or cardiovascular disease.

CROSS REFERENCE TO PRIOR APPLICATION

This application is a Continuation application of U.S. patentapplication Ser. No. 13/984,567 filed on Oct. 7, 2013 under 35 U.S.C.§120, which is a National Stage Application of PCT International PatentApplication No. PCT/KR2012/000935 filed on Feb. 8, 2012 under 35 U.S.C.§371, which claims priority to Korean Patent Application No.10-2011-0011544 filed on Feb. 9, 2011, which are all hereby incorporatedby reference in their entirety.

BACKGROUND

The present invention relates to a novel compound having skin-whitening,anti-oxidizing and PPAR activities and a medical use thereof.

Human skin color is determined according to amounts of melanin,carotene, and hemoglobin, and from among them, melanin acts as the mostdetermining factor. Melanin pigment is a phenol-based polymer materialthat has a composite form of black pigment and protein, and blocksultraviolet light, and people who lacks melanin pigment is verysensitive to sun light and is highly likely to have burns, and even atyoung ages, the possibility of skin cancer is high. Generally,short-wave ultraviolet light and carcinogen form a free radical that isharmful for skin. Melanin removes the free radical to protect proteinsand genes. Accordingly, the wording that melanin is present in greatquintiles means that an effective response system for the protection ofskin from physical or chemical toxicity materials is provided.

Melanin has a circulating cycle: melanin is generated from tyrosine dueto an action of tyrosinase in pigment cells through complicatedprocesses, the generated melanin is transferred to skin cells andconsumed and removed when excoriation occurs. This melanin generationprocess naturally occurs, and in a normal-state skin, excess melanin isnot generated. However, when skin responses to external stimuli, forexample, ultraviolet light, environmental pollution, or stress, excessmelanin is generated so that melanin is not discharged into outside theskin but is transferred to keratinocyte to accumulate in a skinepidermis, thereby causing serious cosmetic problems, such as melasma,freckle, and senile lentigo, promoting skin aging, and inducing skincancer.

Meanwhile, research into the prevention of melanin pigmentation in skinhas been performed in four aspects. First, a tyrosinase synthesisinhibiting material or an antagonist against a matrix of tyrosinase isdeveloped to control the activity of tyrosinase, which is an apoenzymefor melanin synthesis. Second, a material that has toxicity tomelanocyte, in which melanin biosynthesis occurs in animals, isdeveloped to decrease the function of melanocyte. Third, a material thatreduces dopa, which is an intermediate metabolic material of a melaninsynthesis path, is developed to prevent the oxidation of dopa. Finally,an activity of a first enzyme tyrosinase, which is a melanin generator,an activity of a second enzyme DOPA chrome tautomerase that promotesconversion from DOPA chrome to 5,6-dihydroxyindole-2-carboxyic acid(DHICA), and an activity of a third enzyme that promotes conversion fromDHICA to indole-5,6-quinone-2-carboxylic acid are simultaneouslyreduced.

Recently, women in the Asia region desire to have skin that is as whiteand clean as white porcelain, and regard the whiteness and cleanness ascritical criteria for the evaluation of beauty. Accordingly, thedevelopment of whitening agents for the treatment of abnormal skinpigmentation and the satisfaction of cosmetic desires is actively beingperformed.

As a known method of developing a whitening agent, there are adecoloration method performed by reducing a generated melanin pigmentand a method of suppressing activities of tyrosinase, which is an enzymefor forming melanin pigment. However, a whitening agent prepared byusing tocopherol or vitamins to reduce melanin pigment is known to havevery small decoloration effects. Accordingly, an inhibitor thatsuppresses the generation of melanin pigment by inhibiting activities oftyrosinase is getting attention.

In conventional cosmetic fields, as a whitening material, for example, amaterial for suppressing activities of tyrosinase enzyme, such as kojicacid or arbutin, hydroquinone, vitamin C (L-Ascorbic acid) and aderivative thereof, and various plant extracts are used. However, use ofthese materials is limited due to their low stability in a prescriptionsystem, leading to decomposition and pigmentation, generation ofoffensive odor, uncertainty and stability of efficacy and effectivenessat bio-levels. Also, although kojic acid allows a copper ion present inan active site of tyrosinase to adsorb to inhibit enzymatic activities,when mixed in cosmetic products, instability, skin adverse effects, andliver cancer, which was recently identified based on animal tests, mayoccur, and accordingly, use of the kojic acid in cosmetic products wasstopped. Vitamin C and a derivative thereof are highly likely oxidized,and due to this instability, it is difficult for these materials to beused in cosmetic source materials. Hydroquinone has excellent skinwhitening effects. However, it has high skin irritation becausehydroquinone causes allergy, has toxicity to melanin forming cells, andinduces permanent decoloration of skin. Also, in many countries,hydroquinone is defined as carcinogen, and thus, only limitedconcentration of thereof is allowed for use. Arbutin is a derivative inwhich gucopyranoside binds to hydroquinone, and has smaller adverseeffects than when hydroquinone is used, and suppresses synthesis of amelanin pigment without toxicity to human body. Due to suchcharacteristics, its use for the treatment of skin disorders, in whichmelanin pigmentation more occurs, has been suggested. However, arbutinpartly decomposes by skin enzyme. Accordingly, there is a need todevelop an alternative whitening agent that has high efficiency even atsmall concentrations, smaller adverse effects, and stability.

Also, reactive oxygen species (ROS) refers to an in vivo toxic materialassociated with oxygen, and examples of ROS are a free radical, such assuperoxide, hydroxyl, peroxyl, alkoxyl, or hydroperoxyl, and a non-freeradical, such as hydrogen peroxide, hypochlorous acid, ozone, singletoxygen, or peroxynitrite.

From among these ROS, regarding oxygen toxicity, a superoxide freeradical (reactive oxygen or harmful oxygen) is the most frequentlyresearched thereinto and plays a critical role (Fridorich L., Science,201, pp 175-180, 1978). A free radical, which is a strong oxidizinggent, is an unpaired electron. A free radical is generated duringoxidation and reduction reactions of various organisms, and may causedeterioration of eatable oil, or may oxidatively damage on variousbiomaterials (lipid, protein, nucleic acid, carbohydrate) and throughvarious steps, ultimately, mutants may occur (Yen G C et al., J. Agric.Food Chem., 43, pp 27-32, 1995). Regarding an unsaturated fatty acid ofphosphatide which constitutes a biological membrane, a free radical,such as reactive oxygen species, initiates a peroxidative reaction andalso the reaction is proceeds consecutively. Accordingly, a peroxidativereaction due to the free radical may increase permeability of a cellmembrane and cause overall cytotoxicity, thereby inducing aging orpathological phenomenon of aging-associated disorders to be engaged incancer generation process. The action of a radical heavily affectsprogress of various chronic disease, such as atopic disease, cancer,hypertension, myocardial infarction, arteriosclerosis, rheumatis,cataract, Parkinson's disease, which are disorders associated withoxidative stress (DeSouza L C et al., Bioorg. Med. Cehm. Lett., 14, pp5859-5861, 2004), and may weaken the function of an immune system (PikeJ et al., Int. J. Vitam. Nutr. Res., 65, pp 117-120, 1995).

Accordingly, anti-oxidation evaluation on an alternative material forthe prevention from the oxidative damage is very actively performed.Antioxidants do not remove or absorb oxygen, but react with a freeradical so that loss of particular vitamins and necessary amino acids isminimized, and corruption of oil product is delayed or prevented. As asynthetic antioxidant used in foods and medical products, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl galate(PG), and tertiary-butyl hydroquinone (TBHQ) may be used. However, whenthese antioxidants are administered at high concentrations into testanimals, hepatomegaly or cancer may progress. In particular, butylatedhydroxytoluene is known to, based on various study results, increaseenzymatic activity (microsomal enzyme activity in the liver of labanimals), and thus, stability of these phenol-based synthesisantioxidants is debated, and currently, available amounts thereof arelegally limited (Brannen A L, J. Amer. Oil Chem. Soc., 52, pp 59-63,1975; Ito N et al., J. Natl. Cancer Inst., 70, p 343, 1983; Chan K M etal., J. Food. Sci., 58, pp 1-4, 1993). In response, much research intovegetable-originated natural antioxidants that have high antioxidanteffects, are stable, and are prepared at low costs is being performed(Larson R A, Phytochemistry, 27, pp 969-978, 1988). Alongside the recentresearch into natural materials, secondary metabolite that is includedin natural materials is getting attention as a bioactive material, andin particular, research into antioxidants is actively being performed,and examples of known natural antioxidants are tocopherols, flavonoids,gossypols, sesamols, oryzanol, and vitamin C (Huson B et al., FoodChem., 19, pp 537-541, 1987; Frankel, E. N. Food Chem., 57, p 51, 1996;Giese J, Food Technol., 5, pp 73-81, 1996; Pszcczola D E, Food Tech.,55, pp 51-59, 2001). In particular, tocopherol and L-ascorbic acid arepreferred as a natural antioxidant, however, despite its high stability,when used alone, tocopherol has a low oxidation prevention ability(Halliwell B et al., FASEB J., 2, pp 2867-2870, 1988) and is expensive.

Meanwhile, peroxisome is one of intracellular organelles which causeabnormal metabolism functions, and plays a critical role in metabolismof oxygen, glucose, lipid, and hormone, and widely affects controllingof cell proliferation and differentiation, and inflammatory mediators.Also, peroxisome affects, through lipid metabolism and glucosemetabolism, insulin sensitivity, the formation of a cell membrane andmast cells, and oxidative stress, thereby playing a critical role inaging and tumorigenesis. Peroxisome proliferator-activated receptor(PPAR) is one of nuclear receptors that control the expression of genedue to a ligand binding, and various fatty acids act as an endogenousligand. Up to now, three PPAR are known: a peroxisomeproliferator-activated receptor alpha (PPARα), a peroxisomeproliferator-activated receptor beta (PPARβ/δ), and a peroxisomeproliferator-activated receptor gamma (PPARγ)

PPARα generally exists in blood vessel walls, the liver, the heart,muscle, kidney, and brown adipose tissues, and together with fibrates,which is an agonist, PPARα prevents or delays progress ofarteriosclerosis, promotes oxidizing fat to prevent obesity. PPARβ orPPARδ generally exists skin, brain or adipose tissues, is engaged incholestrol antiport, myelination, and cut recovery, and acts as acontroller for fatty acid metabolism and energy homestasis. PPARγgenerally exists in adipose tissues, and also in blood vesselendodermis, macrophage, and β cells of pancreas, and controlsdifferentiation of adipocytes and plays a critical role in body lipidhomestasis. A completely or incompletely activated compound of PPARγsuppresses differentiation of adipocyte to effectively treat obesity,and the incompletely activated compound is effective for the treatmentof hyperglycemia as well as obesity. As described above, to prevent andtreat a variety of disease that is controlled by an action of PPAR,there is a need to develop a novel compound to effectively controlactivities of PPAR.

SUMMARY OF THE INVENTION

Provided are novel compounds having skin-whitening activities.

Provided are novel compounds having anti-oxidant activities.

Provided are novel compounds having PPAR activities.

An embodiment of the present invention provides a compound representedby Formula 1 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, halogen, benzyloxy, acetoxy,O—C(CH₃)₂—COOMe, O—C(CH₃)₂—COOEt, and O—C(CH₃)₂—COOH, X may be any oneof H, a C₁ to C₄ alkyl, CF₃, halogen, carboxyl, COOCH₃,tert-butyldimethylsilyloxy, (oxylane-2-yl)methoxy, nitro, andmethoxybenzyl, and A may be any one of an aromatic ring and aheterocyclic ring, and may be any one selected from the group consistingof thiazole, thiazolidine, dihydrothiazole, benzo[d]thiazole,1H-benzo[d]imidazole, dithiolane, dihydrobenzo[d]thiazole,2H-chromene-2-one, 4H-chromene-4-one and benzo[d]oxazole.

The compound according to the present invention may be a compoundrepresented by Formula 2 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

The compound according to the present invention may be a compoundrepresented by Formula 3 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

The compound according to the present invention may be a compoundrepresented by Formula 4 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

The compound according to the present invention may be a compoundrepresented by Formula 5 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

The compound according to the present invention may be a compoundrepresented by Formula 6 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

The compound according to the present invention may be a compoundrepresented by Formula 7 below:

wherein R¹ to R⁴ may be identical to or different from each other andmay be any one of H, OH, and a C₁ to C₄ alkoxy, and X may be any one ofNH and S.

The compound according to the present invention may be a compoundrepresented by Formula 8 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

The compound according to the present invention may be a compoundrepresented by Formula 9 below:

wherein R¹ to R³ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine, and X may beany one of chlorine and CF₃.

The compound according to the present invention may be a compoundrepresented by Formula 10 below:

wherein X may be any one of hydrogen, chlorine, and trifluoromethyl, andY may be any one of hydrogen and methoxy.

The compound according to the present invention may be a compoundrepresented by Formula 11 below:

wherein X may be any one of hydrogen, chlorine, and trifluoromethyl, andR¹ and R² are different from each other and may be any one of hydrogenand benzyloxy.

The compound according to the present invention may be a compoundrepresented by Formula 12 below:

wherein X may be any one of hydrogen and COOH, Y may be any one ofhydrogen and methoxybenzyl, and R¹ and R² are different from each otherand may be any one of hydrogen, a C₁ to C₄ alkoxy, and benzyloxy.

The compound according to the present invention may be a compoundrepresented by Formula 13 below:

wherein X may be any one of NH, O, and S, Y may be any one of hydrogenand chlorine, and R₁ or R₂ are different from each other and may be anyone of hydrogen, a C₁ to C₄ alkoxy, O—C(CH₃)₂—COOMe, O—C(CH₃)₂—COOEt,and O—C(CH₃)₂—COOH.

The compound according to the present invention may be a compoundrepresented by Formula 14 below:

wherein R¹ and R² may be identical to each other, and may be any one ofOH and OAc.

The compound according to the present invention may be a compoundrepresented by Formula 15 below:

wherein the dotted line (represented by ‘---’) indicates a double bond,R¹ may be any one of hydrogen or methyl, and two substitutes selectedfrom R² through R⁴ may be identical to each other and the identicalsubstitutes may be any one of OH and OAc and the other one may behydrogen.

The compound according to the present invention may be a chromenecompound selected from the group consisting of7,8-bis(tert-butyldimethylsilyloxy)-4-phenyl-2H-chromen-2-one (Compound100), and 3,6-bis((oxiran-2-yl)methoxy)-2-phenyl-4H-chromen-4-one(Compound 106).

The compound according to the present invention may be a compoundrepresented by Formula 16 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

The compound according to the present invention may be a compoundrepresented by Formula 17 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

Compounds according to the present invention have skin-whiteningactivities for the suppression of tyrosinase, and accordingly, may beuseful for use in skin-whitening pharmaceutical composition or cosmeticproducts; have anti-oxidant activities, and accordingly, may be usefulfor the prevention and treatment of skin-aging; and have PPARactivities, and in particular, PPARα and PPARγ activities, andaccordingly, may be useful for use in pharmaceutical compositions orhealth foods which are effective for the prevention and treatment ofobesity, metabolic disease, or cardiovascular disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are graphs showing anti-oxidant activities of a compoundaccording to the present invention.

FIGS. 3 and 4 are graphs showing tyrosinase suppression activities of acompound according to the present invention.

FIGS. 5 and 6 are graphs showing PPARα enhancement activities of acompound according to the present invention.

FIGS. 7 and 8 are graphs showing PPARγ enhancement activities of acompound according to the present invention.

DETAILED DESCRIPTION

An embodiment of the present invention provides a compound representedby Formula 1 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, halogen, benzyloxy, acetoxy,O—C(CH₃)₂—COOMe, O—C(CH₃)₂—COOEt, and O—C(CH₃)₂—COOH, X may be any oneof H, a C₁ to C₄ alkyl, CF₃, halogen, carboxyl, COOCH₃,tert-butyldimethylsilyloxy, (oxylane-2-yl)methoxy, nitro, andmethoxybenzyl, and A may be any one of an aromatic ring and aheterocyclic ring, and may be any one selected from the group consistingof thiazole, thiazolidine, dihydrothiazole, benzo[d]thiazole,1H-benzo[d]imidazole, dithiolane, dihydrobenzo[d]thiazole,2H-chromene-2-one, 4H-chromene-4-one and benzo[d]oxazole.

The compound according to the present invention may be a compoundrepresented by Formula 2 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

In detail, the compound of Formula 2 may be any one selected from thegroup consisting of(2R/S,4R)-2-(4-hydroxyphenyl)thiazolidine-4-carboxylic acid (Compound1); (2R/S,4R)-2-(3,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid(Compound 2); (2R/S,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylicacid] (Compound 3);(2R/S,4R)-2-(4-hydroxy-3-methoxyphenyl)thiazolidine-4-carboxylic acid(Compound 4);(2R/S,4R)-2-(3-ethoxy-4-hydroxyphenyl)thiazolidine-4-carboxylic acid(Compound 5);(2R/S,4R)-2-(3-hydroxy-4-methoxyphenyl)thiazolidine-4-carboxylic acid(Compound 6); (2R/S,4R)-2-(4-methoxyphenyl)thiazolidine-4-carboxylicacid (Compound 7);(2R/S,4R)-2-(3,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid(Compound 8); (2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylicacid (Compound 9);(2R/S,4R)-2-(2-hydroxyphenyl)thiazolidine-4-carboxylic acid (Compound10); (2R/S,4R)-2-(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxylic acid(Compound 11); and(2R/S,4R)-2-(4-hydroxy-3,5-dimethoxyphenyl)thiazolidine-4-carboxylicacid (Compound 12).

The compound according to the present invention may be a compoundrepresented by Formula 3 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

In detail, the compound of Formula 3 may be any one selected from thegroup consisting of 4-(benzo[d]thiazol-2-yl)phenol] (Compound 13);4-(benzo[d]thiazol-2-yl)benzene-1,2-diol (Compound 14);4-(benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 15);4-(benzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 16);4-(benzo[d]thiazol-2-yl)-2-ethoxyphenol (Compound 17);5-(benzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 18);2-(4-methoxyphenyl)benzo[d]thiazol (Compound 19);2-(3,4-dimethoxyphenyl)benzo[d]thiazol (Compound 20);5-(benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 21);2-(2,4-dimethoxyphenyl)benzo[d]thiazol (Compound 22);2-(benzo[d]thiazol-2-yl)phenol (Compound 23);2-(3,4,5-trimethoxyphenyl)benzo[d]thiazol (Compound 24);4-(benzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (Compound 25);4-(benzo[d]thiazol-2-yl)-2-bromophenol (Compound 26); and4-(benzo[d]thiazol-2-yl)-2,6-dibromophenol (Compound 27).

The compound according to the present invention may be a compoundrepresented by Formula 4 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

In detail, the compound of Formula 4 may be any one selected from thegroup consisting of 4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 28);4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,2-diol (Compound29); 4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol(Compound 30);2-methoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound31); 2-ethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 32);2-methoxy-5-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound33); 2-(4-methoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol (Compound34); 2-(3,4-dimethoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol(Compound 35);5-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound36); 2-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol(Compound 37); 2-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 38);5-(trifluoromethyl)-2-(3,4,5-trimethoxyphenyl)benzo[d]thiazol (Compound39); 2,6-dimethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 40); 2-bromo-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 41); and2,6-dibromo-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound42).

The compound according to the present invention may be a compoundrepresented by Formula 5 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

In detail, the compound of Formula 5 may be any one selected from thegroup consisting of 4-(1H-benzo[d]imidazol-2-yl)phenol (Compound 43);4-(1H-benzo[d]imidazol-2-yl)benzene-1,2-diol (Compound 44);4-(1H-benzo[d]imidazol-2-yl)benzene-1,3-diol (Compound 45);4-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenol (Compound 46);4-(1H-benzo[d]imidazol-2-yl)-2-ethoxyphenol (Compound 47);5-(H-benzo[d]imidazol-2-yl)-2-methoxyphenol (Compound 48);2-(4-methoxyphenyl)-1H-benzo[d]imidazole (Compound 49);2-(3,4-dimethoxyphenyl)-1H-benzo[d]imidazole (Compound 50);5-(H-benzo[d]imidazol-2-yl)benzene-1,3-diol (Compound 51);2-(2,4-dimethoxyphenyl)-1H-benzo[d]imidazole (Compound 52);2-(1H-benzo[d]imidazol-2-yl)phenol (Compound 53);2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (Compound 54);4-(1H-benzo[d]imidazol-2-yl)-2,6-dimethoxyphenol (Compound 55); and4-(1H-benzo[d]imidazol-2-yl)-2-bromophenol (Compound 56).

The compound according to the present invention may be a compoundrepresented by Formula 6 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine.

In detail, the compound of Formula 6 may be any one selected from thegroup consisting of2-(4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound57); 2-(3,4-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 58); 2-(2,4-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylicacid (Compound 59);2-(4-hydroxy-3-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 60);2-(3-ethoxy-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 61);2-(3-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 62); 2-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylicacid (Compound 63);2-(3,4-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound64); 2-(2,4-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 65); 2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylicacid (Compound 66);2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 67);2-(4-hydroxy-3,5-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 68);2-(3-bromo-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 69); and2-(3,5-dibromo-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 70).

The compound according to the present invention may be a compoundrepresented by Formula 7 below:

wherein R¹ to R⁴ may be identical to or different from each other andmay be any one of H, OH, and a C₁ to C₄ alkoxy, and X may be any one ofNH and S.

In detail, the compound of Formula 7 may be any one selected from thegroup consisting of 4-(thiazolidin-2-yl)phenol (Compound 71);4-(thiazolidin-2-yl)benzene-1,2-diol (Compound 72);2-methoxy-4-(thiazolidin-2-yl)phenol (Compound 73);2-ethoxy-4-(thiazolidin-2-yl)phenol (Compound 74);2-methoxy-5-(thiazolidin-2-yl)phenol (Compound 75);2-(4-methoxyphenyl)thiazolidine (Compound 76);2-(3,4-dimethoxyphenyl)thiazolidine (Compound 77);2-(2,4-dimethoxyphenyl)thiazolidine (Compound 78);2-(3,4,5-trimethoxyphenyl)thiazolidine (Compound 79);2,6-dimethoxy-4-(thiazolidin-2-yl)phenol (Compound 80); and4-(1,3-dithiolan-2-yl)phenol (Compound 81).

The compound according to the present invention may be a compoundrepresented by Formula 8 below:

R¹ to R⁴ may be identical to or different from each other, and may beany one of H, OH, a C₁ to C₄ alkoxy, and bromine.

In detail, the compound of Formula 8 may be any one selected from thegroup consisting of 4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound82); 4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,2-diol (Compound 83);4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 84);4-(5-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 85);4-(5-chlorobenzo[d]thiazol-2-yl)-2-ethoxyphenol (Compound 86);5-(5-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 87);5-chloro-2-(4-methoxyphenyl)benzo[d]thiazol (Compound 88);5-chloro-2-(3,4-dimethoxyphenyl)benzo[d]thiazol (Compound 89);5-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 90);5-chloro-2-(2,4-dimethoxyphenyl)benzo[d]thiazol (Compound 91);2-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 92);5-chloro-2-(3,4,5-trimethoxyphenyl)benzo[d]thiazol (Compound 93);2-bromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 95);2,6-dibromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 96); and4-(5-chlorobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (Compound 126).

The compound according to the present invention may be a compoundrepresented by Formula 9 below:

wherein R¹ to R³ may be identical to or different from each other, andmay be any one of H, OH, a C₁ to C₄ alkoxy, and bromine, and X may beany one of chlorine and CF₃.

In detail, the compound of Formula 9 may be any one selected from thegroup consisting of4-(5-chloro-2,3-dihydrobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol(Compound 94); and2-bromo-4-(5-(trifluoromethyl)-2,3-dihydrobenzo[d]thiazol-2-yl)phenol(Compound 119).

The compound according to the present invention may be a compoundrepresented by Formula 10 below:

wherein X may be any one of hydrogen, chlorine, and trifluoromethyl, andY may be any one of hydrogen and methoxy.

In detail, the compound of Formula 10 may be any one selected from thegroup consisting of2-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound97);2-methyl-2-(4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenoxy)propanoicacid (Compound 98);2-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid(Compound 99); and2-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-2-methylpropanoic acid(Compound 122) The compound according to the present invention may be acompound represented by Formula 11 below:

wherein X may be any one of hydrogen, chlorine, and trifluoromethyl, andR¹ and R² are different from each other and may be any one of hydrogenand benzyloxy.

In detail, the compound of Formula 11 may be any one selected from thegroup consisting of 2-(4-(benzyloxy)phenyl)benzo[d]thiazol (Compound107); 2-(4-(benzyloxy)phenyl)-5-(trifluoromethyl)benzo[d]thiazol(Compound 108); 2-(4-(benzyloxy)phenyl)-5-chlorobenzo[d]thiazol(Compound 109); 2-(3-(benzyloxy)phenyl)benzo[d]thiazol (Compound 110);2-(3-(benzyloxy)phenyl)-5-(trifluoromethyl)benzo[d]thiazol (Compound111); and 2-(3-(benzyloxy)phenyl)-5-chlorobenzo[d]thiazol (Compound112).

The compound according to the present invention may be a compoundrepresented by Formula 12 below:

wherein X may be any one of hydrogen and COOH, Y may be any one ofhydrogen and methoxybenzyl, and R¹ and R² are different from each otherand may be any one of hydrogen, a C₁ to C₄ alkoxy, and benzyloxy.

In detail, the compound of Formula 12 may be any one selected from thegroup consisting of2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound113); 2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazole (Compound 114);2-(3-(benzyloxy)phenyl)-1H-benzo[d]imidazole (Compound 115);1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1H-benzo[d]imidazole (Compound116); and 2-(3-(benzyloxy)phenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 125).

The compound according to the present invention may be a compoundrepresented by Formula 13 below:

wherein X may be any one of NH, O, and S, Y may be any one of hydrogenand chlorine, and R₁ or R₂ are different from each other and may be anyone of hydrogen, a C₁ to C₄ alkoxy, O—C(CH₃)₂—COOMe, O—C(CH₃)₂—COOEt,and O—C(CH₃)₂—COOH.

In detail, the compound of Formula 13 may be any one selected from thegroup consisting of2-(3-(1H-benzo[d]imidazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound117); 2-(3-(1H-benzo[d]imidazol-2-yl)phenoxy)-2-methylpropanoic acid(Compound 118); 2-(3-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoicacid (Compound 120);2-(3-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid(Compound 121); 4-(benzo[d]oxazol-2-yl)phenol (Compound 123); and2-(4-methoxyphenyl)benzo[d]oxazole (Compound 124).

The compound according to the present invention may be a compoundrepresented by Formula 14 below:

wherein R¹ and R² may be identical to each other, and may be any one ofOH and OAc.

In detail, the compound of Formula 14 may be any one selected from thegroup consisting of (2R/S,4R)-methyl2-(3,4-dihydroxyphenyl)thiazolidine-4-carboxylate (Compound 104); and4-((2R/S,4R)-4-(methoxycarbonyl)thiazolidin-2-yl)-1,2-phenylenediacetate (Compound 105).

The compound according to the present invention may be a compoundrepresented by Formula 15 below:

wherein the doted line (represented by ‘---’) indicates a double bond,R¹ may be any one of hydrogen and methyl, and two substitutes selectedfrom R² through R⁴ may be identical to each other and the identicalsubstitutes may be any one of OH and OAc and the other one may behydrogen.

In detail, the compound of Formula 15 may be any one selected from thegroup consisting of 2-(2,4-dihydroxyphenyl)thiazol-4-carboxylic acid(Compound 101);(4R)-2-(3,4-dihydroxyphenyl)-4,5-dihydrothiazol-4-carboxylic acid(Compound 102); and 4-(4-(methoxycarbonyl)thiazol-2-yl)-1,2-phenylenediacetate (Compound 103).

The compound according to the present invention may be a chromenecompound selected from the group consisting of7,8-bis(tert-butyldimethylsilyloxy)-4-phenyl-2H-chromen-2-one (Compound100), and 3,6-bis((oxiran-2-yl)methoxy)-2-phenyl-4H-chromen-4-one(Compound 106).

The compound according to the present invention may be a compoundrepresented by Formula 16 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

In detail, the compound of Formula 16 may be any one selected from thegroup consisting of 4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenol(Compound 127); 4-(5-methyl-1H-benzo[d]imidazol-2-yl)benzene-1,2-diol(Compound 128); 4-(5-methyl-1H-benzo[d]imidazol-2-yl)benzene-1,3-diol(Compound 129); 2-methoxy-4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenol(Compound 130); 2-(4-methoxyphenyl)-5-methyl-1H-benzo[d]imidazole(Compound 131); 2-(3,4-dimethoxyphenyl)-5-methyl-1H-benzo[d]imidazole(Compound 132); and2-(2,4-dimethoxyphenyl)-5-methyl-1H-benzo[d]imidazole (Compound 133).

The compound according to the present invention may be a compoundrepresented by Formula 17 below:

wherein R¹ to R⁴ may be identical to or different from each other, andmay be any one of H, OH, and a C₁ to C₄ alkoxy.

In detail, the compound of Formula 17 may be any one selected from thegroup consisting of 4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound134); 2-methoxy-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound135); 2-methoxy-5-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound136); 2-(4-methoxyphenyl)-5-nitro-1H-benzo[d]imidazole (Compound 137);and 2,6-dimethoxy-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound138).

The compound may be provided in the form of pharmaceutically acceptablesalts thereof, and for example, may be provided in any salt formselected from the group consisting of hydrochloride, bromate, sulphate,phosphate, nitrate, citrate, acetate, lactate, tartarate, maleate,gluconate, succinate, formate, trifluoroacetate, oxalate, fumarate,methane sulfonate, benzene sulfonate, p-toluene sulfonate, and camphorsulfonate.

Also, the present invention provides a composition for skin-whiteningincluding the compound as an active ingredient. The composition may be apharmaceutical composition or a cosmetic material.

Also, the present invention provides a composition for the prevention ortreatment of oxidation-related disease, the composition including thecompound as an active ingredient. The composition may be apharmaceutical composition or a health food.

The oxidation-related disease may be any one of skin aging, skinpigmentation, wrinkle, psoriasis, and eczema.

Also, the present invention provides a composition for the preventionand treatment of a disease that is regulated by a peroxisomeproliferator-activated receptor (PPAR), the composition including thecompounds as an active ingredient. The composition may be apharmaceutical composition or a health food.

The PPAR may be a peroxisome proliferator-activated receptor alpha(PPARα) or a peroxisome proliferator-activated receptor gamma (PPARγ),and the disease may be any one of obesity, metabolic disease, andcardiovascular disease.

The metabolic disease may be any one selected from hyperlipidemia,diabetes, hyperinsulinemia, hyperuricemia, hypercholesterolemia,hyper-triglyceridemia, Syndrome X, and endothelial dysfunction, and thecardiovascular disease may be any one selected from hypertension,precoagulant state, dyslipidemia, and atherosclerosis disease.

The pharmaceutical composition according to the present invention mayfurther include appropriate carriers, expedient, or diluents which areconventionally used in preparing pharmaceutical compositions.

Examples of carriers, expedient, or diluents that are available for usein the pharmaceutical composition according to the present invention arelactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol,maltitol, starch, Acacia rubber, alginate, gelatin, calcium phosphate,calcium silicate, cellulose, methyl cellulose, microcrystallinecellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate,propylhydroxybenzoate, talc, magnesium stearate, and mineral oils.

The pharmaceutical composition according to the present invention may beprepared into an oral formulation, such as a powder formulation, agranule formulation, a tablet formulation, a capsule formulation, asuspension formulation, an emulsion formulation, a syrup formulation, oran aerosol formulation, an external formulation, a suppositoryformulation, or a sterilized injection solution formation, according toconventional methods.

When prepared into various formulations, a conventional diluent orexpedient, such as a filler, a bulking agent, a binding agent, a wettingagent, an disintegrating agent, or a surfactant, may be used. A solidformulation for oral administration may be a tablet formulation, a pillformulation, a powder formulation, a granule formulation, or a capsuleformulation, and such solid formulations may be prepared by mixing thecompound with one or more expedients selected from, for example, starch,calcium carbonate, sucrose, lactose, and gelatin.

Also, in addition to such expedients, a lubricating agent, such asmagnesium stearate or talc, may be used. A liquid formulation for oraladministration may be a suspension formulation, an internal solutionformulation, an oil formulation, or a syrup formulation, and the liquidformulation may include, in addition to a conventional diluent, such aswater or liquid paraffin, various other expedients, for example, awetting agent, a sweetening agent, a perfuming agent, or a preservative.

A formulation for non-oral administration may be a sterilized aqueoussolution formulation, a non-aqueous solution formulation, a suspensionformulation, an oil formulation, a lyophilized formulation, or asuppository formulation. For use as the non-aqueous solution formulationand the suspension formulation, propyleneglycol, polyethylene glycol,vegetable oil, such as olive oil, an injectable ester such as ethylolatemay be used. As a substrate for the suppository formulation, Witepsol,Macrogol, twin 61, cacao butter, laurin butter, or glycerogelatin may beused.

A dosage of the compound, which is an active ingredient of thepharmaceutical composition according to the present invention, may varyaccording to the age, gender, body weight, and disease of a patient, andthe compositions may be administered in an amount of 0.001 to 100 mg/kg,or 0.01 to 10 mg/kg daily in a bolus or in multiple doses.

Also, a dosage of the compound according to the present invention mayvary according to administration path, severance of disease, gender,body weight, or age. Accordingly, the dosage does not limit the scope ofthe present invention in any aspects.

The pharmaceutical composition may be administered via various pathwaysto mammal, such as rats, mice, livestock, or humans. All of theadministration methods are predictable, and for example, the dosage maybe may be orally administered, or the dosage may be administered byrectal or intravenous, nasal, muscular, subcutaneous, intrauterinesubdural or intracerebroventricular injection.

The compound according to the present invention has a 50% lethalconcentration (LC₅₀) of 2 g/kg or more, and thus stability thereof isguaranteed. Accordingly, the compound may be used in a pharmaceuticalcomposition according to the present invention.

Also, the cosmetic composition may include, in addition to the compoundaccording to the present invention, which is an active ingredient, aconventional auxiliary, such as a stabilizer, a solubilizing agent, avitamin, a pigment, and a fragment, and a perfume.

The cosmetic composition may be prepared in any formulation that isconventionally used in the art. For example, the cosmetic compositionmay be prepared in the formulation of, for example, solution,suspension, emulsion, paste, gel, cream, lotion, powder, oil, powderfoundation, emulsion foundation, wax foundation, and spray, but theformulation thereof is not limited thereto. That is, the cosmeticcomposition may be prepared in the formulation of sun cream, softeningcosmetic water, convergence cosmetic water, nutrition cosmetic water,nutrition cream, massage cream, essence, eye cream, pack, spray, orpowder.

When the formulation is paste, cream, or gel, an available carriercomponent may be, for example, animal oil, vegetable oil, wax, paraffin,starch, tracant, a cellulose derivative, polyethylene glycol, silicon,bentonite, silica, talc, or zinc oxide.

When the formulation is powder or spray, an available carrier componentmay be, for example, lactose, talc, silica, aluminum hydroixde, calciumsilicate, or polyamide powder, and in particular, in the case of spray,additionally, a propellent agent, such as chlorofluorohydrocarbone,propane/butane, or dimethyl ether, may be included.

When the formulation is a solution or an emulsion, an available carriercomponent may be, for example, a solvent, a solubilizing agent, or anemulsifying agent, and a detailed example thereof is water, ethanol,isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylglycol oil, glycerol aliphaticester, polyethyle glycol, or fatty acid ester of sorbitan.

When the formulation is a suspension, an available carrier component maybe, for example, a liquid diluent, such as water, ethanol, or propylene;a suspension, such as ethoxylated isostearyl alcohol, polyoxyethylenesorbitol ester, or polyoxyethylene sorbitan ester; microcrystallinecellulose, aluminium metahydroxide, bentonite, agar, or tracant.

Also, the health food may be provided in the form of powder, granule,tablet, capsule, syrup, or beverage, and the health food may include, inaddition to the compound according to the present invention, which is anactive ingredient, other foods or food additives, and these foods andadditives may be appropriately used according to a conventional method.An amount of the active ingredient may be appropriately determinedaccording to purpose, for example, prevention, health, or therapeutictreatment.

An effective amount of the compound included in the health food may varyaccording to an effective amount of the pharmaceutical composition.However, in the case of a long-term intake for health and sanitation orhealth control purpose, the amount of the compound may be smaller thanthe lower limit of the range. Also, the active ingredient is stable andaccordingly, when used outside the upper limit of the range, stabilityis guaranteed.

The health food is not particularly limited, and examples thereof aremeat, sausage, bread, chocolate, candies, snacks, biscuits, pizza,instant noodles, other noodles, gum, dairy products including ice cream,various soups, beverages, tea, drinks, alcoholic beverage, and vitamincomposites.

Hereinafter, embodiments of the present invention are described indetail by referring to Examples below. However, the examples below areprovided for illustrative purpose only and do not limit the scope of thepresent invention.

Example 1 Synthesis of Compounds 1 to 12

Table 1 below is provided to explain substitution patterns of Compounds1 to 12, which are 2-(substituted phenyl)thiazolidine-4-carboxylic acidanalog, synthesized in the following examples.

TABLE 1 Compound R¹ R² R³ R⁴ 1 H H OH H 2 H OH OH H 3 OH H OH H 4 H OMeOH H 5 H OEt OH H 6 H OH OMe H 7 H H OMe H 8 H OMe OMe H 9 OMe H OMe H10 OH H H H 11 H OMe OMe OMe 12 H OMe OH OMe

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 1, 2, and 4 to 12 was performed as follows. Indetail, in an ethanol (EtOH) (5 to 30 ml) solvent, a suspension ofsubstituted benzaldhehyde (1.53 to 2.46 mmol) and L-cysteine (1.0 or 1.5eq.) was refluxed for 1.5 to 48 hours. The produced precipitate wasfiltered, and in consideration of characteristics of the remainingstarting materials, a filter cake was washed with ethanol, methylenechloride, water, ethyl acetate(ethyl acetate), and/or methanol (MeOH) toobtain a target product (yield: 9.9 to 78.6%). A synthesis method ofCompound 3 was separately described below.

Example 1-1 Synthesis of(2R/S,4R)-2-(4-hydroxyphenyl)thiazolidine-4-carboxylic acid (Compound 1)

White solid; a reaction time of 13 hours; a yield of 50.0%; a meltingpoint of 161.8 to 164.4° C., ¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (br s,1H), 9.39 (br s, 1H), 7.27 (d, 2H, J=8.8 Hz), 7.20 (d, 2H, J=8.4 Hz),6.70 (d, 2H, J=8.4 Hz), 6.66 (d, 2H, J=8.4 Hz), 5.49 (s, 1H), 5.36 (s,1H), 4.21 (dd, 1H, J=4.4, 7.6 Hz), 3.79 (dd, 1H, J=7.6, 8.4 Hz), 3.30(dd, 1H, J=7.2, 10.0 Hz), 3.23 (dd, 1H, J=7.2, 10.4 Hz), 3.11 (dd, 1H,J=4.4, 10.4 Hz), 3.00 (t, 1H, J=8.4, 10.0 Hz); ¹³C NMR (100 MHz,DMSO-d₆) δ 173.8, 173.0, 158.1, 157.6, 131.4, 129.5, 129.2, 129.0,115.8, 115.6, 72.5, 72.0, 65.9, 65.4, 39.2, 38.5; LRMS(ESI) m/z 224(M−H)⁻.

Example 1-2 Synthesis of(2R/S,4R)-2-(3,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid(Compound 2)

White solid; a reaction time of 12 hours; a yield of 77.3%; a meltingpoint of 195.5 to 196.8° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (br s,2H), 8.89 (br s, 2H), 6.88 (d, 1H, J=1.5 Hz), 6.83 (s, 1H), 6.73 (dd,1H, J=1.5, 8.0 Hz), 6.68 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0 Hz), 6.64(d, 1H, J=2.5, 8.5 Hz), 5.46 (s, 1H), 5.32 (s, 1H), 4.21 (dd, 1H, J=4.0,7.0 Hz), 3.82 (t, 1H, J=8.0 Hz), 3.33 (dd, 1H, J=7.0, 10.0 Hz), 3.23(dd, 1H, J=7.0, 10.0 Hz), 3.11 (dd, 1H, J=4.0, 10.5 Hz), 2.94 (t, 1H,J=9.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 173.8, 173.2, 146.1, 145.9,145.6, 145.6, 132.1, 130.1, 118.9, 118.7, 116.0, 115.7, 115.2, 115.1,72.7, 72.1, 65.9, 65.4, 39.3, 38.4; LRMS(ES) m/z 240 (M−H)⁻.

Example 1-3 Synthesis of(2R/S,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid(Compound 3)

In a mixed solvent including ethanol (10 ml) and water (10 ml), asolution including 2,4-dihydroxybenzaldehyde (943 mg, 6.83 mmol),L-cysteine hydrochloride monohydrate (1.0 g, 5.69 mmol), and sodiumacetate (495 mg, 6.03 mmol) was stirred at room temperature for 14hours. The produced precipitate was filtered, and a filter cake waswashed with water, and ethyl acetate to obtain the target product thatis a solid white (1.316 g, 95.8%).

White solid; a reaction time of 14 hours; a yield of 95.8%; a meltingpoint of >300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (br s, 2H), 9.19 (brs, 2H), 7.11 (d, 1H, J=8.0 Hz), 7.08 (d, 1H, J=8.5 Hz), 6.27 (d, 1H,J=2.5 Hz), 6.24 (d, 1H, J=2.0 Hz), 6.20 (dd, 1H, J=2.5, 8.5 Hz), 6.18(dd, 1H, J=2.5, 8.0 Hz), 5.74 (s, 1H), 5.57 (s, 1H), 4.23 (dd, 1H,J=4.5, 7.0 Hz), 3.77 (dd, 1H, J=7.0, 8.5 Hz), 3.31 (dd, 1H, J=7.5, 10.0Hz), 3.20 (dd, 1H, J=7.0, 10.0 Hz), 3.07 (dd, 1H, J=4.0, 10.0 Hz), 2.94(t, 1H, J=9.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 173.7, 173.2, 158.8,158.3, 156.9, 156.3, 129.5, 128.2, 117.9, 115.2, 107.1, 106.8, 103.4,103.0, 68.6, 66.5, 65.6, 65.2, 38.9, 37.6; LRMS(ES) m/z 240 (M−H)⁻.

Example 1-4 Synthesis of(2R/S,4R)-2-(4-hydroxy-3-methoxyphenyl)thiazolidine-4-carboxylic acid(Compound 4)

White solid; a reaction time of 48 hours; a yield of 42.7%; a meltingpoint of 166.6-168.4° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (br s, 1H),8.97 (br s, 1H), 7.10 (d, 1H, J=1.5 Hz), 7.01 (d, 1H, J=2.0 Hz), 6.88(dd, 1H, J=2.0, 8.0 Hz), 6.83 (dd, 1H, J=1.5, 8.0 Hz), 6.72 (d, 1H,J=8.0 Hz), 6.69 (d, 1H, J=8.0 Hz), 5.52 (s, 1H), 5.39 (s, 1H), 4.27 (dd,1H, J=4.0, 7.5 Hz), 3.83 (dd, 1H, J=7.5, 8.5 Hz), 3.76 (s, 3H), 3.75 (s,3H), 3.32 (dd, 1H, J=6.5, 9.5 Hz), 3.27 (dd, 1H, J=7.5, 10.5 Hz), 3.15(dd, 1H, J=3.5, 10.5 Hz), 3.05 (dd, 1H, J=9.5 Hz); ¹³C NMR (100 MHz,DMSO-d₆) δ 173.8, 172.9, 148.2, 148.0, 147.3, 146.8, 132.0, 130.2,120.6, 120.3, 115.8, 115.7, 112.2, 112.0, 72.8, 72.2, 66.1, 65.4, 56.4,56.3, 39.1, 38.4; LRMS(ES) m/z 254 (M−H)⁻.

Example 1-5 Synthesis of(2R/S,4R)-2-(3-ethoxy-4-hydroxyphenyl)thiazolidine-4-carboxylic acid(Compound 5)

White solid; a reaction time of 3 hours; a yield of 77.7%; a meltingpoint of 174.3-175.9° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 2H), 7.06(d, 1H, J=2.0 Hz), 6.97 (d, 1H, J=2.0 Hz), 6.84 (dd, 1H, J=2.0, 8.0 Hz),6.79 (dd, 1H, J=2.4, 8.4 Hz), 6.70 (d, 1H, J=8.0 Hz), 6.67 (d, 1H, J=8.0Hz), 5.47 (s, 1H), 5.34 (s, 1H), 4.23 (dd, 1H, J=3.6, 7.2 Hz), 3.99-3.94(m, 4H), 3.79 (dd, 1H, J=7.2, 8.8 Hz), 3.32 (dd, 1H, J=7.2, 10.4 Hz),3.23 (dd, 1H, J=7.2, 10.0 Hz), 3.12 (dd, 1H, J=3.6, 10.0 Hz), 3.01 (t,1H, J=9.6 Hz), 1.28 (t, 3H, J=7.2 Hz), 1.28 (t, 3H, J=6.8 Hz); ¹³C NMR(100 MHz, DMSO-d₆) δ 173.8, 172.9, 147.6, 147.3, 147.1, 147.1, 131.9,130.1, 120.7, 120.4, 115.9, 115.7, 113.5, 113.3, 72.8, 72.2, 66.1, 65.4,64.6, 64.6, 39.0, 38.4, 15.4, 15.4; LRMS(ES) m/z 268 (M−H)⁻.

Example 1-6 Synthesis of(2R/S,4R)-2-(3-hydroxy-4-methoxyphenyl)thiazolidine-4-carboxylic acid(Compound 6)

White solid; a reaction time of 8 hours; a yield of 78.6%; a meltingpoint of 146.9-149.8° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (br s, 1H),8.96 (br s, 1H), 6.92 (s, 1H), 6.87 (m, 3H), 6.83 (d, 1H, J=8.0 Hz),6.80 (d, 1H, J=8.0 Hz), 5.51 (s, 1H), 5.36 (s, 1H), 4.20 (dd, 1H, J=4.5,6.5 Hz), 3.83 (dd, 1H, J=7.5, 8.5 Hz), 3.75 (s, 3H), 3.73 (s, 3H), 3.33(dd, 1H, J=7.5, 9.5 Hz), 3.25 (dd, 1H, J=7.5, 10.0 Hz), 3.10 (dd, 1H,J=4.0, 10.0 Hz), 3.02 (t, 1H, J=9.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ173.8, 173.1, 148.3, 147.8, 147.1, 146.9, 134.0, 131.8, 118.8, 118.4,115.0, 115.0, 112.6, 112.4, 72.5, 71.8, 65.9, 65.5, 56.3, 56.3, 39.2,38.5; LRMS(ES) m/z 254 (M−H)⁻.

Example 1-7 Synthesis of(2R/S,4R)-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid (Compound 7)

White solid; a reaction time of 48 hours; a yield of 40.5%; a meltingpoint of 157.6-158.2° C.; ¹H NMR (500 MHz, II) δ 7.43 (d, 2H, J=8.5 Hz),7.35 (d, 2H, J=8.5 Hz), 6.91 (d, 2H, J=8.5 Hz), 6.87 (d, 2H, J=9.0 Hz),5.58 (s, 1H), 5.44 (s, 1H), 4.23 (dd, 1H, J=4.0, 7.5 Hz), 3.85 (dd, 1H,J=2.0, 8.5 Hz), 3.74 (s, 3H), 3.73 (s, 3H), 3.34 (dd, 1H, J=7.0, 10.0Hz), 3.27 (dd, 1H, J=7.0, 10.0 Hz), 3.14 (dd, 1H, J=4.0, 10.0 Hz), 3.05(dd, 1H, J=8.5, 10.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 173.8, 172.9,159.9, 159.4, 133.4, 131.4, 129.3, 129.0, 114.5, 114.2, 72.2, 71.6,66.0, 65.5, 55.8, 55.8, 39.2, 38.5; LRMS(ES) m/z 238 (M−H)⁻.

Example 1-8 Synthesis of(2R/S,4R)-2-(3,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid(Compound 8)

White solid; a reaction time of 10 hours; a yield of 57.0%; a meltingpoint of 173.6-175.4° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.15 (d, 1H, J=2.0Hz), 7.04 (d, 1H, J=2.0 Hz), 7.01 (dd, 1H, J=2.0, 8.0 Hz), 6.96 (dd, 1H,J=2.0, 8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.87 (d, 1H, J=8.5 Hz), 5.57 (s,1H), 5.43 (s, 1H), 4.28 (dd, 1H, J=4.0, 7.5 Hz), 3.85 (dd, 1H, J=7.0,9.0 Hz), 3.75 (s, 3H), 3.74 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 3.33(dd, 1H, J=7.0, 10.0 Hz), 3.28 (dd, 1H, J=7.5, 10.5 Hz), 3.16 (dd, 1H,J=4.0, 10.5 Hz), 3.06 (t, 1H, J=9.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ173.8, 172.9, 149.4, 149.3, 149.2, 149.0, 133.6, 131.8, 120.3, 119.9,112.1, 112.0, 111.7, 111.5, 72.6, 72.0, 66.2, 65.5, 56.2, 56.1, 39.0,38.5; LRMS(ES) m/z 268 (M−H)⁻.

Example 1-9 Synthesis of(2R/S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid(Compound 9)

White solid; a reaction time of 1.5 hours; a yield of 34.7%; a meltingpoint of 137.7-139.2° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 7.39 (d, 1H, J=8.5Hz), 7.29 (d, 1H, J=8.0 Hz), 6.56 (d, 1H, J=1.5 Hz), 6.53 (dd, 1H,J=1.5, 8.5 Hz), 6.52 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=1.5, 8.5 Hz),5.78 (s, 1H), 5.62 (s, 1H), 4.18 (t, 1H, J=6.0 Hz), 3.79 (dd, 1H, J=7.5,8.5 Hz), 3.78 (s, 3H), 3.77 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.31(dd, 1H, J=7.0, 10.0 Hz), 3.17 (dd, 1H, J=7.0, 10.0 Hz), 2.99 (dd, 1H,J=5.0, 10.0 Hz), 2.95 (t, 1H, J=9.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ173.7, 173.1, 161.1, 160.5, 158.4, 157.9, 129.0, 127.1, 122.6, 119.3,105.7, 105.2, 99.3, 99.0, 67.2, 66.0, 65.7, 65.6, 56.3, 56.2, 55.9,55.9, 39.0, 37.9; LRMS(ES) m/z 268 (M−H)⁻.

Example 1-10 Synthesis of(2R/S,4R)-2-(2-hydroxyphenyl)thiazolidine-4-carboxylic acid (Compound10)

White solid; a reaction time of 6 hours; a yield of 75.0%; a meltingpoint of 173.2-175.1° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.90 (br s, 2H),7.33 (dd, 1H, J=1.0, 8.0 Hz), 7.28 (d, 1H, J=7.5 Hz), 7.12 (td, 1H,J=1.5, 8.0 Hz), 7.05 (td, 1H, J=1.5, 8.0 Hz), 6.81-6.73 (m, 4H), 5.83(s, 1H), 5.64 (s, 1H), 4.20 (dd, 1H, J=5.5, 6.5 Hz), 3.82 (dd, 1H,J=7.0, 9.0 Hz), 3.33 (dd, 1H, J=7.0, 10.0 Hz), 3.19 (dd, 1H, J=7.0, 10.5Hz), 3.01 (dd, 1H, J=5.0, 10.0 Hz), 2.96 (t, 1H, J=10.0 Hz); ¹³C NMR(100 MHz, DMSO-d₆) 173.6, 173.1, 155.8, 155.3, 129.7, 128.8, 128.5,126.7, 120.1, 119.7, 119.4, 117.9, 116.3, 115.7, 68.3, 66.3, 65.9, 65.5,38.9, 37.7; LRMS(ES) m/z 224 (M−H)⁻.

Example 1-11 Synthesis of(2R/S,4R)-2-(3,4,5-trimethoxyphenyl)thiazolidine-4-carboxylic acid(Compound 11)

White solid; a reaction time of 5 hours; a yield of 9.9%; a meltingpoint of 197.0-199.7° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 6.85 (s, 2H), 6.76(s, 2H), 5.57 (s, 1H), 5.42 (s, 1H), 4.28 (dd, 1H, J=4.0, 7.0 Hz), 3.85(dd, 1H, J=6.5, 8.5 Hz), 3.77 (s, 6H), 3.76 (s, 6H), 3.64 (s, 3H), 3.63(s, 3H), 3.32 (dd, 1H, J=6.5, 9.5 Hz), 3.29 (dd, 1H, J=7.0, 10.0 Hz),3.15 (dd, 1H, J=4.0, 10.5 Hz), 3.07 (t, 1H, J=9.5 Hz); ¹³C NMR (100 MHz,DMSO-d₆) δ 173.8, 172.8, 153.4, 153.3, 137.9, 137.5, 137.1, 135.3,105.5, 105.0, 72.8, 72.1, 66.4, 65.5, 60.6, 60.6, 56.6, 56.5, 38.9,38.5; LRMS(ES) m/z 298 (M−H)⁻.

Example 1-12 Synthesis of(2R/S,4R)-2-(4-hydroxy-3,5-dimethoxyphenyl)thiazolidine-4-carboxylicacid (Compound 12)

White solid; a reaction time of 4 hours; a yield of 69.7%; a meltingpoint of 139.6-141.0° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.42 (br s, 2H),6.79 (s, 2H), 6.72 (s, 2H), 5.52 (s, 1H), 5.39 (s, 1H), 4.30 (dd, 1H,J=3.5, 7.5 Hz), 3.83 (t, 1H, J=8.0 Hz), 3.75 (s, 6H), 3.74 (s, 6H), 3.32(dd, 1H, J=7.0, 9.5 Hz), 3.28 (dd, 1H, J=7.5, 10.5 Hz), 3.17 (dd, 1H,J=3.5, 10.5 Hz), 3.06 (t, 1H, J=9.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ173.9, 172.9, 148.4, 148.3, 136.2, 135.7, 131.0, 129.3, 105.7, 105.3,73.1, 72.5, 66.2, 65.5, 56.7, 56.7, 39.0, 38.4; LRMS(ES) m/z 284 (M−H)⁻.

Example 2 Synthesis of Compounds 13 to 27

Table 2 below is provided to explain substitution patterns of Compounds13 to 27, which are 2-(substituted phenyl)benzo[d]thiazole analogs.

TABLE 2 Compound R¹ R² R³ R⁴ 13 H H OH H 14 H OH OH H 15 OH H OH H 16 HOMe OH H 17 H OEt OH H 18 H OH OMe H 19 H H OMe H 20 H OMe OMe H 21 H OHH OH 22 OMe H OMe H 23 OH H H H 24 H OMe OMe OMe 25 H OMe OH OMe 26 H BrOH H 27 H Br OH Br

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 13, 20, and 22 to 25 was performed as follows. Ina methanol (3 to 7 mL) solvent, 2-aminothiophenol (1.60 mmol) was addedto a suspension of substituted benzaldhehyde (1.33 mmol), and thereaction mixture was stirred at room temperature for 5 to 96 hours. Thework-up of the reaction was performed by using one of the followingthree methods A through C.

Method A: methanol was evaporated, and then, the resultant solid wasfiltered and a filter cake was washed with hexane, methylene chloride,ethyl acetate, and/or cold methanol.

Method B: methanol was evaporated, and then, the residual was dissolvedin small amounts of methylene chloride, ethyl acetate and/or coldmethanol, and then, hexane was added thereto. After cooling, theresultant precipitate was filtered, and the filtered product was washedwith hexane, methylene chloride, ethyl acetate and/or cold methanol.

Method C: methanol was evaporated until its volume reduced in halfthereof, and then, the reaction mixture was preserved in a cooler or,before the preservation in the cooler, water (20 mL) was added to thereaction mixture. The resultant precipitate was filtered, and a filtercake was washed with hexane, methylene chloride, ethyl acetate and/orcold methanol.

In the case of several compounds (Compounds 23 and 25), flash columnchromatography (hexane/methylene chloride=4/1 to 2/1, Compound 23;methylene chloride/methanol=90/1, and then, methylene chloride, Compound25) was performed thereon for purification. The target products(Compounds 13-20, and 22-24) were obtained in a yield of 15.2 to 82.6%However, synthesis methods of Compounds 21, 26 and 27, which aredifferent from the method described above, are separately describedbelow.

Example 2-1 Synthesis of 4-(benzo[d]thiazol-2-yl)phenol (Compound 13)

Light yellow solid; a reaction time of 22 h; a yield of 28.5%; a meltingpoint of 228.0-229.3° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.94-7.92 (m, 4H),7.49 (td, 1H, J=1.0, 7.6 Hz), 7.38 (td, 1H, J=1.0, 7.6 Hz), 6.91 (d, 2H,J=8.0 Hz); ¹³C NMR (100 MHz, CD₃OD) δ169.2, 160.8, 153.8, 134.5, 129.1,126.3, 124.9, 124.8, 121.9, 121.6, 115.8; LRMS(ESI) m/z 228 (M+H)⁺.

Example 2-2 Synthesis of 4-(benzo[d]thiazol-2-yl)benzene-1,2-diol(Compound 14)

Bright Yellowish green solid; a reaction time of 96 hours; a yield of61.5%; a melting point of 219.2-219.9° C.; ¹H NMR (400 MHz, CD₃OD) δ7.90-7.87 (m, 2H), 7.50 (d, 1H, J=2.4 Hz), 7.44 (td, 1H, J=1.2, 8.4 Hz),7.40 (dd, 1H, J=2.4, 8.0 Hz), 7.33 (td, 1H, J=1.2, 8.4 Hz), 6.86 (d, 1H,J=8.0 Hz); ¹³C NMR (100 MHz, CD₃OD) δ 169.4, 153.8, 149.1, 145.8, 134.5,126.3, 125.1, 124.9, 121.9, 121.5, 120.0, 115.5, 114.0; LRMS(ESI) m/z244 (M+H)⁺.

Example 2-3 Synthesis of 4-(benzo[d]thiazol-2-yl)benzene-1,3-diol(Compound 15)

White solid; a reaction time of 20 hours; a yield of 15.2%; a meltingpoint of 197.7-198.5° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.90 (ddd, 1H,J=0.8, 1.2, 8.0 Hz), 7.87 (ddd, 1H, J=0.8, 1.2, 8.0 Hz), 7.58 (dd, 1H,J=0.4, 8.4 Hz), 7.46 (td, 1H, J=1.2, 7.2 Hz), 7.35 (td, 1H, J=1.2, 7.2Hz), 6.41 (dd, 1H, J=2.4, 8.4 Hz), 6.39 (d, 1H, J=2.4 Hz); ¹³C NMR (100MHz, CD₃OD) δ 169.5, 162.2, 159.7, 151.8, 132.3, 129.9, 126.5, 125.0,121.4, 121.1, 109.5, 108.2, 102.8; LRMS(ESI) m/z 244 (M+H)⁺.

Example 2-4 Synthesis of 4-(benzo[d]thiazol-2-yl)-2-methoxyphenol(Compound 16)

Green solid; a reaction time of 22 hours; a yield of 55.6%; a meltingpoint of 171.4-173.6° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.93-7.91 (m, 2H),7.67 (d, 1H, J=2.4 Hz), 7.49 (dd, 1H, J=2.0, 8.4 Hz), 7.47 (td, 1H,J=1.2, 7.6 Hz), 7.36 (td, 1H, J=1.2, 7.6 Hz), 6.89 (d, 1H, J=8.0 Hz),3.95 (s, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 169.3, 153.7, 150.2, 148.4,134.5, 126.4, 125.0, 125.0, 121.9, 121.6, 121.5, 115.5, 109.9, 55.3;LRMS(ESI) m/z 258 (M+H)⁺.

Example 2-5 Synthesis of 4-(benzo[d]thiazol-2-yl)-2-ethoxyphenol(Compound 17)

Light gray solid; a reaction time of 20 hours; a yield of 36.2%; amelting point of 125.6-126.5° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.92 (d, 1H,J=8.5 Hz), 7.91 (d, 1H, J=8.0 Hz), 7.65 (d, 1H, J=1.5 Hz), 7.49-7.46 (m,2H), 7.36 (td, 1H, J=1.0, 8.0 Hz), 6.90 (d, 1H, J=8.0 Hz), 4.19 (q, 2H,J=7.0 Hz), 1.47 (t, 3H, J=7.0 Hz); ¹³C NMR (100 MHz, CD₃OD) δ168.5,152.9, 149.5, 146.6, 133.7, 125.5, 124.3, 124.1, 121.1, 120.7, 120.7,114.8, 110.4, 63.8, 13.0; LRMS(ESI) m/z 272 (M+H)⁺.

Example 2-6 Synthesis of 5-(benzo[d]thiazol-2-yl)-2-methoxyphenol(Compound 18)

Light gray solid; a reaction time of 20 hours; a yield of 39.3%; amelting point of 171.6-172.2° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.94-7.92(m, 2H), 7.53 (dd, 1H, J=2.0, 8.0 Hz), 7.52 (d, 1H, J=2.0 Hz), 7.47 (td,1H, J=1.2, 8.4 Hz), 7.37 (td, 1H, J=1.2, 8.4 Hz), 7.04 (d, 1H, J=8.4Hz), 3.91 (s, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 169.0, 153.8, 150.9,147.1, 134.6, 126.4, 125.1, 125.1, 122.1, 121.6, 119.6, 113.7, 111.5,55.3; LRMS(ESI) m/z 258 (M+H)⁺.

Example 2-7 Synthesis of 2-(4-methoxyphenyl)benzo[d]thiazole (Compound19)

White solid; a reaction time of 5 hours; a yield of 15.8%; a meltingpoint of 121.3-121.9° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.06-8.04 (m, 3H),7.87 (d, 1H, J=8.0 Hz), 7.48 (td, 1H, J=1.0, 8.0 Hz), 7.36 (td, 1H,J=1.0, 7.5 Hz), 7.00 (d, 2H, J=9.0 Hz), 3.88 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 168.2, 162.2, 154.2, 135.0, 129.4, 126.5, 125.1, 125.1, 123.0,121.7, 114.6, 55.7; LRMS(ESI) m/z 242 (M+H)⁺.

Example 2-8 Synthesis of 2-(3,4-dimethoxyphenyl)benzo[d]thiazole(Compound 20)

White solid; a reaction time of 22 hours; a yield of 27.9%; a meltingpoint of 135.0-137.2° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, 1H, J=8.0Hz), 7.85 (d, 1H, J=8.0 Hz), 7.71 (d, 1H, J=1.6 Hz), 7.57 (dd, 1H,J=2.0, 8.4 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 6.91 (d,1H, J=8.4 Hz), 4.00 (s, 3H), 3.93 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ168.2, 154.1, 151.9, 149.6, 134.9, 126.7, 1266.5, 125.2, 123.0, 121.7,121.4, 111.2, 110.0, 56.4, 56.3; LRMS(ESI) m/z 272 (M+H)⁺.

Example 2-9 Synthesis of 5-(benzo[d]thiazol-2-yl)benzene-1,3-diol(Compound 21)

An acetic acid (0.8 mL) and sodium acetate (196.6 mg, 2.40 mmol) wereadded to a suspension including 3,5-dihydroxybenzaldehyde (91.6 mg, 0.66mmol) and 2-aminothiophenol (0.095 mL, 0.80 mmol, purity: 90%), andthen, the reaction mixture was refluxed for 2 hours. The resultantprecipitate was filtered, and the filtered product was washed with waterand methylene chloride to obtain a gray solid Compound 21 (78.3 mg,48.6%).

Gray solid; a reaction time of 2 hours; a yield of 48.6%; a meltingpoint of 274.5-276.5° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.94 (d, 1H, J=8.4Hz), 7.92 (d, 1H, J=8.4 Hz), 7.47 (t, 1H, J=7.6 Hz), 7.37 (t, 1H, J=7.6Hz), 6.98 (s, 2H), 6.42 (s, 1H); ¹³C NMR (100 MHz, CD₃OD) δ 169.2,159.2, 153.6, 134.9, 134.7, 126.4, 125.4, 122.4, 121.7, 105.7, 105.4;LRMS(ESI) m/z 244 (M+H)⁺.

Example 2-10 Synthesis of 2-(2,4-dimethoxyphenyl)benzo[d]thiazole(Compound 22)

Very light yellow solid; a reaction time of 22 hours; a yield of 35.8%;a melting point of 137.4-138.9° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.50 (d,1H, J=8.5 Hz), 8.07 (d, 1H, J=8.0 Hz), 7.90 (d, 1H, J=7.5 Hz), 7.48 (t,1H, J=7.0 Hz), 7.35 (t, 1H, J=7.0 Hz), 6.69 (d, 1H, J=8.5 Hz), 6.59 (s,1H), 4.04 (s, 3H), 3.90 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.6,163.3, 158.9, 151.9, 135.6, 131.1, 126.1, 124.5, 122.4, 121.3, 115.6,106.2, 98.7, 55.9, 55.8; LRMS(ESI) m/z 272 (M+H)⁺.

Example 2-11 Synthesis of 2-(benzo[d]thiazol-2-yl)phenol (Compound 23)

White solid; a reaction time of 21 hours; a yield of 42.9%; a meltingpoint of 132.6-133.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 12.26 (s, 1H), 7.97(ddd, 1H, J=0.4, 1.2, 8.0 Hz), 7.89 (ddd, 1H, J=0.8, 1.2, 8.0 Hz), 7.68(dd, 1H, J=1.6, 7.6 Hz), 7.49 (ddd, 1H, J=1.2, 7.2, 8.4 Hz), 7.41-7.35(m, 2H), 7.09 (dd, 1H, J=0.8, 8.4 Hz), 6.94 (ddd, 1H, J=1.2, 7.6, 8.0Hz); ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 158.2, 152.1, 133.0, 132.8,128.6, 126.9, 125.8, 122.4, 121.7, 119.7, 118.8, 117.0; LRMS(ESI) m/z228 (M+H)⁺.

Example 2-12 Synthesis of 2-(3,4,5-trimethoxyphenyl)benzo[d]thiazole(Compound 24)

White solid; a reaction time of 21 hours; a yield of 28.3%; a meltingpoint of 149.5-151.1° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, 1H, J=8.4Hz), 7.87 (d, 1H, J=8.0 Hz), 7.47 (td, 1H, J=1.2, 7.2 Hz), 7.36 (td, 1H,J=1.2, 8.4 Hz), 7.31 (s, 2H), 3.97 (s, 6H), 3.91 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 168.0, 154.2, 153.8, 135.2, 129.3, 126.6, 125.3, 123.3,123.3, 121.8, 105.0, 61.2, 56.6; LRMS(ESI) m/z 302 (M+H)⁺.

Example 2-13 Synthesis of 4-(benzo[d]thiazol-2-yl)-2,6-dimethoxyphenol(Compound 25)

Bright brown solid; a reaction time of 16 hours; a yield of 82.6%; amelting point of 153.5-156.1° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (dd,1H, J=0.8, 8.0 Hz), 7.81 (dd, 1H, J=0.4, 7.6 Hz), 7.42 (td, 1H, J=1.2,7.2 Hz), 7.30 (td, 1H, J=1.2, 7.6 Hz), 7.29 (s, 2H), 6.47 (br s, 1H),3.89 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 154.2, 147.6, 138.1,134.9, 126.5, 125.1, 125.1, 123.0, 121.7, 104.8, 56.6; LRMS(ESI) m/z 288(M+H)⁺.

Example 2-14 Synthesis of 4-(benzo[d]thiazol-2-yl)-2-bromophenol(Compound 26)

In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.)and 3-bromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at roomtemperature. The produced precipitate was filtered and the filteredproduct was washed with cold methanol to obtain Compound 26.

Light Lemon-colored solid; a reaction time of 19 hours; a yield of38.0%; a melting point of 190.6-191.7° C.; ¹H NMR (500 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 8.08 (d, 1H, J=8.0 Hz), 7.99 (d,1H, J=8.0 Hz), 7.89 (dd, 1H, J=2.0, 8.5 Hz), 7.50 (t, 1H, J=7.5 Hz),7.41 (t, 1H, J=7.5 Hz), 7.10 (d, 1H, J=8.5 Hz); ¹³C NMR (100 MHz,DMSO-d₆) δ 166.5, 157.7, 154.2, 134.9, 132.0, 128.9, 127.3, 126.1,125.9, 123.2, 122.9, 117.5, 110.8.

Example 2-15 Synthesis of 4-(benzo[d]thiazol-2-yl)-2,6-dibromophenol(Compound 27)

In a methanol solvent, a solution including 2-aminothiophenol (1.0 eq.)and 3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) was stirred at roomtemperature. The produced precipitate was filtered and the filteredproduct was washed with cold methanol to obtain Compound 27.

A reaction time of 7 hours; a yield of 16.0%; ¹H NMR (500 MHz, DMSO-d₆)δ 10.76 (s, 1H), 8.17 (s, 2H), 8.12 (d, 1H, J=8.0 Hz), 8.01 (d, 1H,J=8.0 Hz), 7.53 (t, 1H, J=8.0 Hz), 7.44 (t, 1H, J=8.0 Hz) ¹³C NMR (100MHz, DMSO-d₆) δ 164.9, 154.1, 154.0, 135.2, 131.4, 127.7, 127.4, 126.2,123.5, 123.0, 113.1.

Example 3 Synthesis of Compounds 28 to 42

Table 3 below is provided to explain substitution patterns of Compounds28 to 42, which are 2-(substitutedphenyl)-5-(trifluoromethyl)benzo[d]thiazole analogs.

TABLE 3 Compound R¹ R² R³ R⁴ 28 H H OH H 29 H OH OH H 30 OH H OH H 31 HOMe OH H 32 H OEt OH H 33 H OH OMe H 34 H H OMe H 35 H OMe OMe H 36 H OHH OH 37 OMe H OMe H 38 OH H H H 39 H OMe OMe OMe 40 H OMe OH OMe 41 H BrOH H 42 H Br OH Br

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis methods of Compounds 28 to 35 and 37 to 40 are as follows. Indetail, in a methyl alcohol (5 mL) solvent, a mixture of2-amino-4-(trifluoromethyl)benzenethiol (100 mg, 0.44 mmol) andsubstituted benzaldhehyde (0.8 to 1.0 eq.) was stirred at roomtemperature for 4 to 15 hours. After the solvent was evaporated, theresidual was solidified by using methyl alcohol and/or methylenechloride and/or water, and then, the result was preserved at atemperature of 0° C. The produced precipitate was filtered, and inconsideration of physical characteristics of the remaining startingmaterials, the filtered product was washed with iced water and/ormethylene chloride and/or cold methyl alcohol to obtain a solid targetproduct. In the case of Compound 30, after the reaction solvent wasremoved, the residual was purified by silica gel column chromatographyusing hexane and ethyl acetate (4:1) as a developer to obtain a solidCompound 30.

However, synthesis methods of Compounds 36, 41 and 42, which aredifferent from the method described above, are separately describedbelow.

Example 3-1 Synthesis of4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound 28)

White solid; a reaction time of 5.5 hours; a yield of 58.1%; a meltingpoint of 187.2-188.9° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.18 (d, 1H, J=1.0Hz), 8.11 (d, 1H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz), 7.62 (dd, 1H,J=1.0, 9.0 Hz), 6.92 (d, 2H, J=8.5 Hz); ¹³C NMR (100 MHz, CD₃OD) δ171.4, 161.4, 153.7, 138.5, 129.4, 128.7 (q, J=31.8 Hz), 124.5 (q,J=269.3 Hz), 124.2, 122.7, 120.9 (q, J=3.8 Hz), 118.8 (q, J=4.5 Hz),115.9; ¹⁹F NMR (470 MHz, CD₃OD) δ −63.66.

Example 3-2 Synthesis of4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,2-diol (Compound29)

Gray solid; a reaction time of 7.5 hours; a yield of 64.3%; a meltingpoint of 267.3-269.4° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.14 (s, 1H), 8.07(d, 1H, J=8.5 Hz), 7.59 (dd, 1H, J=1.0, 8.5 Hz), 7.53 (d, 1H, J=2.5 Hz),7.42 (dd, 1H, J=2.5, 8.0 Hz), 6.88 (d, 1H, J=8.0 Hz); ¹³C NMR (100 MHz,CD₃OD) δ 171.7, 153.2, 149.7, 145.9, 138.3, 128.8 (q, J=32.7 Hz), 124.5(q, J=270.0 Hz), 124.4, 122.7, 120.9 (q, J=3.8 Hz), 120.4, 118.6 (q,J=3.8 Hz), 115.6, 114.1; ¹⁹F NMR (470 MHz, CD₃OD) δ −63.64.

Example 3-3 Synthesis of4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound30)

White solid; a reaction time of 7 hours; a yield of 50.2%; a meltingpoint of 236.2-238.2° C.; ¹H NMR (400 MHz, CD₃OD) δ 8.16 (s, 1H), 8.10(d, 1H, J=8.4 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.60 (d, 1H, J=8.4 Hz), 6.43(dd, 1H, J=2.4, 8.8 Hz), 6.40 (d, 1H, J=2.0 Hz); ¹³C NMR (100 MHz,CD₃OD) δ 171.5, 159.8, 151.9, 153.8, 136.6, 130.2, 128.6 (q, J=31.1 Hz),124.5 (q, J=270.0 Hz), 122.4, 120.8 (q, J=3.8 Hz), 118.0 (q, J=4.6 Hz),116.2, 108.5, 102.8; ¹⁹F NMR (470 MHz, CD₃OD) δ −63.65.

Example 3-4 Synthesis of2-methoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound31)

Yellow solid; a reaction time of 5 hours; a yield of 43.8%; a meltingpoint of 155.7-159.9° C.; ¹H NMR (400 MHz, CD₃OD) δ 8.15 (dd, 1H, J=0.8,1.6 Hz), 8.11 (dd, 1H, J=0.8, 8.8 Hz), 7.65 (d, 1H, J=2.4 Hz), 7.63 (dd,1H, J=1.2, 8.8 Hz), 7.51 (dd, 1H, J=2.0, 8.4 Hz), 6.89 (d, 1H, J=8.0Hz), 3.93 (s, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 172.2, 151.6, 151.3,148.5, 137.5, 129.2 (q, J=31.8 Hz), 124.4 (q, J=270.0 Hz), 123.1, 123.1,122.4, 121.5 (q, J=3.8 Hz), 117.9 (q, J=4.5 Hz), 115.8, 110.2, 55.4; ¹⁹FNMR (470 MHz, CD₃OD) δ −63.72.

Example 3-5 Synthesis of2-ethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound 32)

Greenish yellow solid; a reaction time of 6 hours; a yield of 28.8%; amelting point of 117.0-117.8° C.; ¹H NMR (400 MHz, CD₃OD) δ 8.10 (dd,1H, J=0.8, 1.6 Hz), 8.03 (dd, 1H, J=0.8, 8.4 Hz), 7.58 (d, 1H, J=2.0Hz), 7.56 (dd, 1H, J=1.6, 8.4 Hz), 7.44 (dd, 1H, J=2.0, 8.0 Hz), 6.87(d, 1H, J=8.0 Hz), 4.13 (q, 2H, J=7.2 Hz), 1.44 (t, 3H, J=7.2 Hz); ¹³CNMR (100 MHz, CD₃OD) δ 171.5, 153.3, 150.9, 147.5, 138.3, 128.7 (q,J=31.9 Hz), 124.5 (q, J=270.6 Hz), 124.3, 122.6, 121.8, 120.9 (q, J=3.7Hz), 118.6 (q, J=4.5 Hz), 115.6, 111.1, 64.5, 13.8; ¹⁹F NMR (470 MHz,CD₃OD) δ −63.63.

Example 3-6 Synthesis of2-methoxy-5-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound33)

Greenish yellow solid; a reaction time of 7 hours; a yield of 55.9%; amelting point of 142.1-144.5° C.; ¹H NMR (400 MHz, CD₃OD) δ 8.16 (s,1H), 8.12 (d, 1H, J=8.4 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.54 (dd, 1H,J=2.0, 8.4 Hz), 7.52 (d, 1H, J=2.0 Hz), 7.03 (d, 1H, J=8.4 Hz), 3.91 (s,3H); ¹³C NMR (100 MHz, CD₃OD) δ 171.5, 152.9, 151.6, 147.2, 138.3, 128.9(q, J=32.6 Hz), 125.3, 124.5 (q, J=270.1 Hz), 122.9, 121.2 (q, J=3.8Hz), 120.2, 118.6 (q, J=3.8 Hz), 113.8, 111.6, 55.3; ¹⁹F NMR (470 MHz,CD₃OD) δ −63.66.

Example 3-7 Synthesis of2-(4-methoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound 34)

White solid; a reaction time of 10 hours; a yield of 67.7%; a meltingpoint of 128.8-130.1° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.28 (s, 1H), 8.03(d, 2H, J=8.5 Hz), 7.96 (d, 1H, J=8.0 Hz), 7.58 (dd, 1H, J=1.0, 8.5 Hz),7.01 (d, 2H, J=8.5 Hz), 3.89 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.1,162.6, 154.1, 138.5, 129.5, 129.0 (q, J=31.9 Hz), 126.0, 124.5 (q,J=270.9 Hz), 122.3, 121.3 (q, J=3.0 Hz), 120.1 (q, J=3.8 Hz), 114.7,55.7; ¹⁹F NMR (470 MHz, CD₃OD) δ −66.09;

Example 3-8 Synthesis of2-(3,4-dimethoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound35)

White solid; a reaction time of 7 hours; a yield of 37.6%; a meltingpoint of 120.4-121.6° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.29 (s, 1H), 7.98(d, 1H, J=8.5 Hz), 7.72 (d, 1H, J=2.0 Hz), 7.61 (dd, 1H, J=2.0, 8.5 Hz),7.59 (d, 1H, J=8.5 Hz), 6.96 (d, 1H, J=8.5 Hz), 4.03 (s, 3H), 3.97 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.1, 154.0, 152.3, 149.7, 138.1, 128.8(q, J=33.4 Hz), 126.2, 124.5 (q, J=270.1 Hz), 122.3, 121.7, 121.4 (q,J=3.8 Hz), 120.2 (q, J=4.3 Hz), 111.3, 110.0, 56.4, 56.3; ¹⁹F NMR (470MHz, CDCl₃) δ −62.17.

Example 3-9 Synthesis of5-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound36)

In an acetic acid (0.42 mL) solvent, a mixture including2-amino-4-(trifluoromethyl)benzenethiol (100 mg, 0.44 mmol),3,5-dihydroxybenzaldehyde (60 mg, 0.44 mmol), and sodium acetate (107mg, 1.30 mmol) was refluxed for 6.5 hours. After cooling, the reactionmixture was distributed between ethyl acetate and water, and an organiclayer was dried by using MgSO₄, filtered, and evaporated under reducedpressure. The residual was purified by silica gel column chromatographyusing hexane and ethyl acetate (2:1) as a developer to obtain a solidCompound 36 (50.6 mg, 37%).

Gray solid; a reaction time of 6.5 hours; a yield of 37.3%; a meltingpoint of 256.7-260.6° C.; ¹H NMR (400 MHz, CD₃OD) δ 8.24 (s, 1H), 8.16(d, 1H, J=8.4 Hz), 7.66 (d, 1H, J=8.0 Hz), 7.02 (d, 2H, J=2.4 Hz), 6.44(t, 1H, J=2.0 Hz); ¹³C NMR (100 MHz, CD₃OD) δ 171.5, 159.3, 153.5,134.4, 134.4, 128.9 (q, J=31.9 Hz), 124.0 (q, J=270.7 Hz), 122.9, 121.4(q, J=3.6 Hz), 119.4 (q, J=3.8 Hz), 105.8, 105.8; ¹⁹F NMR (470 MHz,CD₃OD) δ −63.70.

Example 3-10 Synthesis of2-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound37)

White solid; a reaction time of 4 hours; a yield of 34.2%; a meltingpoint of 140.4-141.6° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, 1H, J=9.0Hz), 8.29 (s, 1H), 7.98 (d, 1H, J=8.0 Hz), 7.56 (d, 1H, J=8.0 Hz), 6.69(dd, 1H, J=2.5, 9.0 Hz), 6.59 (d, 1H, J=2.5 Hz), 4.05 (s, 3H), 3.90 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 163.6, 159.0, 152.0, 139.2,131.1, 128.6 (q, J=32.6 Hz), 124.7 (q, J=270.1 Hz), 121.9, 120.6 (q,J=3.8 Hz), 119.6 (q, J=4.5 Hz), 115.3, 106.4, 98.7, 55.9, 55.8; ¹⁹F NMR(470 MHz, CDCl₃) δ −61.99.

Example 3-11 Synthesis of2-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound 38)

White solid; a reaction time of 15 hours; a yield of 47.4%; a meltingpoint of 175.0-176.5° C.; ¹H NMR (500 MHz, CDCl₃) δ 12.15 (s, 1H), 8.25(s, 1H), 8.01 (d, 1H, J=8.5 Hz), 7.68 (dd, 1H, J=1.0, 8.0 Hz), 7.64 (dd,1H, J=0.5, 8.0 Hz), 7.42 (td, 1H, J=1.5, 8.0 Hz), 7.12 (d, 1H, J=8.5Hz), 6.98 (t, 1H, J=7.5 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 171.6, 158.3,151.8, 136.2, 133.7, 129.7 (q, J=32.6 Hz), 128.8, 124.9 (q, J=270.0 Hz),122.4, 122.1 (q, J=3.0 Hz), 120.0, 119.5 (q, J=3.8 Hz), 118.3, 116.5;¹⁹F NMR (470 MHz, CDCl₃) δ −62.23.

Example 3-12 Synthesis of5-(trifluoromethyl)-2-(3,4,5-trimethoxyphenyl)benzo[d]thiazole (Compound39)

White solid; a reaction time of 7 hours; a yield of 65.4%; a meltingpoint of 132.5-134.0° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.31 (s, 1H), 7.98(d, 1H, J=8.0 Hz), 7.60 (d, 1H, J=8.5 Hz), 7.33 (s, 2H), 3.99 (s, 6H),3.94 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.0, 153.9, 153.9, 141.4,138.6, 129.2 (q, J=32.7 Hz), 128.6, 124.4 (q, J=270.9 Hz), 122.4, 121.6(q, J=3.1 Hz), 120.4 (q, J=3.8 Hz), 105.1, 61.2, 56.6; ¹⁹F NMR (470 MHz,CDCl₃) δ −62.19.

Example 3-13 Synthesis of2,6-dimethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 40)

Yellow solid; a reaction time of 7 hours; a yield of 27.7%; a meltingpoint of 220.6-222.6° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.19 (s, 1H), 8.14(d, 1H, J=8.5 Hz), 7.64 (d, 1H, J=8.5 Hz), 7.37 (s, 2H), 3.95 (s, 6H);¹³C NMR (100 MHz, CD₃OD) δ 171.6, 153.3, 148.5, 139.8, 138.5, 128.9 (q,J=31.9 Hz), 124.5 (q, J=270.0 Hz), 123.3, 122.8, 121.1 (q, J=3.0 Hz),118.7 (q, J=3.8 Hz), 105.0, 55.8; ¹⁹F NMR (470 MHz, CD₃OD) δ −63.68.

Example 3-14 Synthesis of2-bromo-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound 41)

In a N,N-dimethylformamide (DMF) solvent, a suspension of3-bromo-4-hydroxybenzaldehyde (1.0 eq.) and2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at atemperature of 100° C. After cooling, DMF was removed therefrom underreduced pressure. Methylene chloride was added to the resultant solid,and the produced precipitate was filtered, and washed with methylenechloride to obtain a solid target product.

A reaction time of 8 hours; a yield of 49.2%; ¹H NMR (400 MHz, DMSO-d₆)δ 11.21 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 8.23 (s, 1H), 8.13 (s, 1H),7.85 (d, 1H, J=8.4 Hz), 7.65 (d, 1H, J=8.4 Hz), 7.08 (d, 1H, J=8.4 Hz);¹³C NMR (100 MHz, DMSO-d₆) δ 169.1, 158.2, 153.7, 139.0, 132.2, 129.1,128.1 (q, J=31.8 Hz), 125.4, 124.9 (q, J=270.8 Hz), 124.2, 121.7 (d,J=3.1 Hz), 119.8 (d, J=3.8 Hz), 117.5, 110.9.

Example 3-15 Synthesis of2,6-dibromo-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound42)

In a N,N-dimethylformamide (DMF) solvent, a suspension of3,5-dibromo-4-hydroxybenzaldehyde (1.0 eq.) and2-amino-4-(trifluoromethyl)benzenethiol (1.0 eq.) was heated at atemperature of 100° C. After cooling, DMF was removed therefrom underreduced pressure. Methylene chloride was added to the resultant solid,and the produced precipitate was filtered, and washed with methylenechloride to obtain a solid target product.

A reaction time of 13 hours; a yield of 13.24%; ¹H NMR (500 MHz,DMSO-d₆) δ 10.85 (s, 1H), 8.31 (d, 1H, J=7.5 Hz), 8.27 (s, 1H), 8.13 (s,2H), 7.70 (d, 1H, J=8.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.6, 154.8,153.5, 139.3, 131.6, 128.2 (q, J=31.8 Hz), 126.7, 124.9 (q, J=270.9 Hz),124.4 (d, J=4.5 Hz), 122.1, 120.1, 113.1.

Example 4 Synthesis of Compounds 43 to 56

Table 4 below is provided to explain substitution patterns of Compounds43 to 56, which are 2-(substituted phenyl)-1H-benzo[d]imidazolederivatives.

TABLE 4 Compound R¹ R² R³ R⁴ 43 H H OH H 44 H OH OH H 45 OH H OH H 46 HOMe OH H 47 H OEt OH H 48 H OH OMe H 49 H H OMe H 50 H OMe OMe H 51 H OHH OH 52 OMe H OMe H 53 OH H H H 54 H OMe OMe OMe 55 H OMe OH OMe 56 H BrOH H

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 43 to 55 was performed as follows. In detail, ina DMF (2 mL) solvent, a mixture including 1,2-phenylenediamine (100 mg,0.92 mmol), substituted benzaldehyde (1.0 eq.), and Na₂S₂O₅ (1.0 eq.)was heated at a temperature of 70 to 80° C. for 1 to 4.5 hours. AfterDMF was evaporated, the residual was distributed between ethyl acetateand water, and an organic layer was dried by using MgSO₄, filtered, andevaporated under reduced pressure. In consideration of physicalcharacteristics of the remaining starting materials, the result wassolidified by using methylene chloride and/or water and/or ethylacetate. The precipitate was filtered to obtain a solid target product.

However, synthesis method of Compound 56, which is different from themethod described above, is separately described below.

Example 4-1 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)phenol (Compound43)

White solid; a reaction time of 4 hours; a yield of 22.4%; a meltingpoint of 284.6 to 285.7° C.; ¹H NMR (400 MHz, CD₃OD) δ 7.90 (d, 2H,J=8.8 Hz), 7.50 (dd, 2H, J=2.8, 6.0 Hz), 7.15 (dd, 2H, J=2.8, 6.0 Hz),6.91 (d, 2H, J=8.8 Hz); ¹³C NMR (100 MHz, CD₃OD) δ 159.8, 152.7, 138.8,128.4, 122.4, 120.9, 115.8, 114.3.

Example 4-2 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)benzene-1,2-diol(Compound 44)

Light brown; a reaction time of 1.5 hours; a yield of 37.2%; a meltingpoint of 268.5 to 269.8° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (br s,1H), 9.45 (s, 1H), 9.22 (s, 1H), 7.57 (d, 1H, J=2.0 Hz), 7.48 (dd, 2H,J=2.8, 6.0 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.10 (dd, 2H, J=2.8, 6.0 Hz),6.84 (d, 1H, J=2.0, 8.4 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 152.6, 148.1,146.2, 139.3, 122.2, 122.2, 118.9, 116.4, 115.1, 114.8.

Example 4-3 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)benzene-1,3-diol(Compound 45)

Bright yellow; a reaction time of 1 hours; a yield of 46.2%; a meltingpoint of 279.4 to 280.1° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.64 (br s,1H), 9.67 (br s, 2H), 7.82 (d, 1H, J=8.4 Hz), 7.55 (dd, 2H, J=3.2, 5.6Hz), 7.19 (dd, 2H, J=3.2, 6.0 Hz), 6.43 (dd, 1H, J=2.0, 8.4 Hz), 6.38(d, 1H, J=2.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 161.5, 160.6, 153.1,139.3, 128.1, 123.0, 115.5, 108.2, 105.2, 103.7.

Example 4-4 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenol(Compound 46)

Beige solid; a reaction time of 2 hours; a yield of 30.2%; a meltingpoint of 220.5 to 221.7° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.64 (br s,1H), 9.58 (br s, 1H), 7.77 (s, 1H), 7.64 (d, 1H, J=8.0 Hz), 7.55 (br s,2H), 7.15 (br s, 2H), 6.94 (d, 1H, J=8.0 Hz), 3.88 (s, 3H); ¹³C NMR (100MHz, DMSO-d₆) δ 152.5, 149.1, 148.5, 139.3, 122.4, 122.1, 120.4, 116.4,115.6, 111.1, 56.3.

Example 4-5 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-ethoxyphenol(Compound 47)

Light lemon; a reaction time of 4 hours; a yield of 67.0%; a meltingpoint of 174.0 to 174.6° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (br s,1H), 9.48 (s, 1H), 7.70 (s, 1H), 7.59 (d, 1H, J=8.4 Hz), 7.50 (dd, 2H,J=3.2, 6.0 Hz), 7.12 (dd, 2H, J=3.2, 6.0 Hz), 6.90 (d, 1H, J=8.4 Hz),4.12 (q, 2H, J=6.8 Hz), 1.35 (t, 3H, J=6.8 Hz)l; ¹³C NMR (100 MHz,DMSO-d₆) δ 152.5, 149.4, 147.7, 135.7, 122.4, 122.1, 120.4, 118.4,116.5, 112.2, 64.6, 15.4.

Example 4-6 Synthesis of 5-(1H-benzo[d]imidazol-2-yl)-2-methoxyphenol(Compound 48)

White solid; a reaction time of 2.5 hours; a yield of 45.0% meltingpoint, 249.7 to 250.7° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s, 1H),9.29 (br s, 1H), 7.61 (d, 1H, J=2.0 Hz), 7.57 (d, 1H, J=2.0, 7.2 Hz),7.50 (dd, 2H, J=2.8, 6.0 Hz), 7.12 (dd, 2H, J=2.8, 6.0 Hz), 7.04 (d, 1H,J=7.2 Hz), 3.80 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ152.2, 150.0,147.3, 139.3, 123.6, 122.4, 118.6, 115.1, 114.4, 112.8, 56.3.

Example 4-7 Synthesis of 2-(4-methoxyphenyl)-1H-benzo[d]imidazole(Compound 49)

White solid; a reaction time of 4.5 hours; a yield of 24.2%; a meltingpoint of 226.4 to 227.8° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (br s,1H), 8.14 (d, 2H, J=8.8 Hz), 7.56 (dd, 2H, J=3.2, 6.0 Hz), 7.15 (dd, 2H,J=3.2, 6.0 Hz), 7.08 (d, 2H, J=8.8 Hz), 3.79 (s, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 161.3, 152.1, 138.8, 128.7, 123.4, 122.4, 115.0, 115.0, 55.9.

Example 4-8 Synthesis of 2-(3,4-dimethoxyphenyl)-1H-benzo[d]imidazole(Compound 50)

Yellowish white crystal; a reaction time of 2.5 hours; a yield of 39.9%;a melting point of 219.0 to 221.6° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.63(br s, 1H), 7.77 (d, 1H, J=2.0 Hz), 7.74 (dd, 1H, J=2.0, 9.0 Hz), 7.56(dd, 2H, J=3.0, 6.0 Hz), 7.17 (dd, 2H, J=3.0, 6.0 Hz), 7.12 (d, 1H,J=8.5 Hz), 3.87 (s, 3H), 3.83 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ152.1, 151.0, 149.6, 139.3, 123.4, 122.5, 120.0, 115.1, 112.5, 110.4,56.3, 56.3.

Example 4-9 Synthesis of 5-(1H-benzo[d]imidazol-2-yl)benzene-1,3-diol(Compound 51)

Light brown of a mixture of beige and brown; a reaction time of 3.5hours; a yield of 16.2%; a melting point of >300° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.62 (br s, 1H), 9.53 (s, 2H), 7.52 (dd, 2H, J=3.2, 6.4 Hz),7.15 (dd, 2H, J=3.2, 6.4 Hz), 7.01 (d, 2H, J=2.0 Hz), 6.33 (t, 1H, J=2.0Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.4, 152.2, 139.3, 132.3, 122.7,115.8, 105.5, 104.9.

Example 4-10 Synthesis of 2-(2,4-dimethoxyphenyl)-1H-benzo[d]imidazole(Compound 52)

Beige solid; a reaction time of 2.5 hours; a yield of 40.7%; a meltingpoint of 197.5 to 198.8° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.65 (br s,1H), 8.27 (d, 1H, J=9.0 Hz), 7.59 (dd, 2H, J=3.0, 6.0 Hz), 7.16 (dd, 2H,J=3.0, 6.0 Hz), 6.75 (s, 1H), 6.71 (dd, 1H, J=2.5, 9.0 Hz), 4.01 (s,3H), 3.85 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.7, 158.8, 149.9,139.3, 131.6, 122.2, 115.5, 111.6, 106.9, 99.2, 56.5, 56.1.

Example 4-11 Synthesis of 2-(1H-benzo[d]imidazol-2-yl)phenol (Compound53)

Orange; a reaction time of 2 hours; a yield of 37.0%; a melting point of237.3 to 241.0° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.63 (br s, 1H), 8.01(d, 1H, J=7.6 Hz), 7.63 (dd, 2H, J=3.2, 6.0 Hz), 7.34 (t, 1H, J=7.6 Hz),7.25 (dd, 2H, J=3.2, 6.0 Hz), 7.00 (d, 1H, J=8.4 Hz), 6.98 (t, 1H, J=7.2Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ158.7, 152.3, 139.3, 132.4, 126.9,123.5, 119.8, 117.9, 115.1, 113.2.

Example 4-12 Synthesis of2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole (Compound 54)

Beige-ish white; a reaction time of 2 hours; a yield of 21.1%; a meltingpoint of 257.0 to 257.7° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s,1H), 7.57 (dd, 2H, J=3.2, 5.6 Hz), 7.50 (s, 2H), 7.17 (dd, 2H, J=3.2,6.0 Hz), 3.87 (s, 6H), 3.70 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ153.9,151.9, 139.6, 138.0, 126.1, 122.7, 115.1, 104.5, 60.8, 56.7.

Example 4-13 Synthesis of4-(1H-benzo[d]imidazol-2-yl)-2,6-dimethoxyphenol (Compound 55)

Ivory; a reaction time of 2 hours; a yield of 48.7%; a melting point of193.6 to 195.1° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (br s, 1H), 8.87(s, 1H), 7.52 (dd, 2H, J=2.8, 5.6 Hz), 7.45 (s, 2H), 7.13 (dd, 2H,J=2.8, 6.0 Hz), 3.85 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ 152.5, 148.9,139.4, 138.2, 122.4, 120.9, 115.1, 104.7, 56.8.

Example 4-14 Synthesis of 4-(1H-benzo[d]imidazol-2-yl)-2-bromophenol(Compound 56)

In a DMF (3 mL) solvent, a mixture including 1,2-phenylenediamine (100mg, 0.92 mmol), 3-bromo-4-hydroxybenzaldehyde (187.8 mg, 0.92 mmol), andNa₂S₂O₅ (177.6 mg, 0.92 mmol) was mixed at a temperature of 80° C. for 1hour. After cooling, DMF was removed therefrom under reduced pressure.Methylene chloride and water were added thereto to obtain a solidproduct, and the precipitate was filtered, and the filtered product waswashed with methylene chloride, ethyl acetate, and water to obtain asolid Compound 56 (79.4%).

A reaction time of 1 hour; a yield of 79.4%; ¹H NMR (500 MHz, DMSO-d₆) δ10.84 (s, 1H), 8.29 (s, 1H), 7.99 (d, 1H, J=8.4 Hz), 7.52 (m, 2H), 7.14(m, 2H), 7.07 (d, 1H, J=8.4 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 156.3,151.0, 139.8, 131.6, 127.9, 123.4, 122.6, 117.3, 115.5, 110.4.

Example 5 Synthesis of Compounds 57 to 70

Table 5 below is provided to explain substitution patterns of Compounds57 to 70, which are 2-(substitutedphenyl)-1H-benzo[d]imidazole-5-carboxylic acid derivatives.

TABLE 5 Compound R¹ R² R³ R⁴ 57 H H OH H 58 H OH OH H 59 OH H OH H 60 HOMe OH H 61 H OEt OH H 62 H OH OMe H 63 H H OMe H 64 H OMe OMe H 65 OMeH OMe H 66 OH H H H 67 H OMe OMe OMe 68 H OMe OH OMe 69 H Br OH H 70 HBr OH Br

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 57 to 70 was performed as follows. In detail, asolution including 3,4-diaminobenzoic acid (1.0 eq.), substitutedbenzaldhehyde (1.0 eq.), and Na₂S₂O₅ (1.0 eq.) was heated in ananhydrous DMF at a temperature of 80° C. After cooling, DMF was removedtherefrom under reduced pressure. The residual was distributed betweenethyl acetate and water, and an organic layer was dried by using MgSO₄,filtered, and evaporated. The filtrate was evaporated, and the resultantsolid was filtered and washed with water and methylene chloride and/orethyl acetate to obtain a target product.

Example 5-1 Synthesis of2-(4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound 57)

Beige solid; a reaction time of 3 hours; a yield of 66.0%; a meltingpoint of >300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.91 (s, 1H), 12.62 (s,1H), 10.02 (s, 1H), 8.09 (br s, 1H), 8.01 (d, 2H, J=8.5 Hz), 7.78 (d,1H, J=8.0 Hz), 7.57 (br s, 1H), 6.92 (d, 2H, J=8.5 Hz).

Example 5-2 Synthesis of2-(3,4-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound58)

A reaction time of 6 hours; a yield of 11.6%; ¹H NMR (500 MHz, DMSO-d₆)δ12.58 (s, 1H), 9.56 (s, 1H), 9.29 (s, 1H), 8.10 (s, 1H), 7.79 (d, 1H,J=8.5 Hz), 7.61 (s, 1H), 7.57 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=7.5 Hz),6.89 (d, 1H, J=8.0 Hz).

Example 5-3 Synthesis of2-(2,4-dihydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound59)

Yellow solid; a reaction time of 4.2 hours; a yield of 57.1%; a meltingpoint of >300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 2H), 10.08 (s,1H), 8.15 (s, 1H), 7.87 (d, 1H, J=9.0 Hz), 7.85 (d, 1H, J=9.0 Hz), 7.63(d, 1H, J=8.5 Hz), 6.47 (d, 1H, J=8.5 Hz), 6.43 (s, 1H).

Example 5-4 Synthesis of2-(4-hydroxy-3-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 60)

Light brown solid; a reaction time of 6 hours; a yield of 39.6%; amelting point of >300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.91 (s, 1H),9.67 (s, 1H), 8.14 (br s, 1H), 7.82 (d, 1H, J=8.5 Hz), 7.77 (s, 1H),7.66 (d, 1H, J=8.0 Hz), 7.62 (d, 1H, J=8.5 Hz), 6.97 (d, 1H, J=7.0 Hz),3.89 (s, 3H).

Example 5-5 Synthesis of2-(3-ethoxy-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 61)

Light yellow solid; a reaction time of 4.2 hours; a yield of 57.1%; amelting point of >300° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.91 (s, 1H),9.56 (s, 1H), 8.10 (s, 1H), 7.78 (d, 1H, J=8.4 Hz), 7.71 (s, 1H), 7.61(d, 1H, J=8.4 Hz), 7.57 (d, 1H, J=8.0 Hz), 6.92 (d, 1H, J=8.4 Hz), 4.11(q, 2H, J=6.8 Hz), 1.36 (t, 3H, J=6.8 Hz).

Example 5-6 Synthesis of3-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 62)

Light brown solid; a reaction time of 4 hours; a yield of 72.6%; amelting point of 246.6 to 247.7° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.95(s, 1H), 9.39 (s, 1H), 8.15 (s, 1H), 7.82 (dd, 1H, J=1.5, 8.5 Hz), 7.66(d, 1H, J=2.5 Hz), 7.62 (dd, 1H, J=2.0, 8.5 Hz), 7.61 (d, 1H, J=8.5 Hz),7.09 (d, 1H, J=8.5 Hz), 3.84 (s, 3H).

Example 5-7 Synthesis of2-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound 63)

Ivory white solid; a reaction time of 4 hours; a yield of 20.7%; amelting point of 264.7 to 265.4° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 12.91(s, 1H), 8.10 (m, 3H), 7.78 (d, 1H, J=8.4 Hz), 7.58 (br s, 1H), 7.10 (d,2H, J=9.2 Hz), 3.81 (s, 3H);

Example 5-8 Synthesis of2-(3,4-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound64)

A reaction time of 4.5 hours; a yield of 78.6%; ¹H NMR (400 MHz,DMSO-d₆) δ 12.84 (s, 2H), 8.15 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.75 (s,1H), 7.74 (d, 1H, J=9.2 Hz), 7.60 (d, 1H, J=8.0 Hz), 7.08 (d, 1H, J=7.6Hz), 3.85 (s, 3H), 3.79 (s, 3H).

Example 5-9 Synthesis of2-(2,4-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound65)

A reaction time of 5 hours; a yield of 77.6%; ¹H NMR (400 MHz, DMSO-d₆)δ 12.18 (s, 1H), 8.26 (d, 1H, J=8.4 Hz), 8.20 (s, 1H), 7.78 (d, 1H,J=8.4 Hz), 7.60 (d, 1H, J=8.4 Hz), 6.73 (s, 1H), 6.69 (d, 1H, J=9.2 Hz),3.99 (s, 3H), 3.82 (s, 3H).

Example 5-10 Synthesis of2-(2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound 66)

A reaction time of 4.5 hours; a yield of 45.5%; ¹H NMR (400 MHz,DMSO-d₆) δ 12.92 (s, 3H), 8.21 (s, 1H), 8.05 (d, 1H, J=8.0 Hz), 7.87 (d,1H, J=8.4 Hz), 7.69 (d, 1H, J=8.0 Hz), 7.37 (t, 1H, J=7.6 Hz), 7.03 (d,1H, J=8.4 Hz), 6.99 (t, 1H, J=7.2 Hz).

Example 5-11 Synthesis of2-(3,4,5-trimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 67)

A reaction time of 4 hours; a yield of 61.4%; ¹H NMR (400 MHz, DMSO-d₆)δ 8.16 (s, 1H), 7.83 (d, 1H, J=8.0 Hz), 7.64 (d, 1H, J=8.4 Hz), 7.51 (s,2H), 3.88 (s, 6H), 3.72 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 168.4,154.0, 154.0, 142.5, 140.2, 139.5, 125.5, 125.0, 124.4, 117.5, 115.0,104.9, 60.8, 56.8.

Example 5-12 Synthesis of4-hydroxy-3,5-dimethoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 68)

Beige solid; a reaction time of 6 hours; a yield of 52.8%; a meltingpoint of 280.0 to 281.4° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 12.97 (s, 1H),9.05 (s, 1H), 8.15 (s, 1H), 7.82 (d, 1H, J=8.0 Hz), 7.62 (d, 1H, J=7.5Hz), 7.51 (s, 1H), 7.50 (s, 1H), 3.88 (s, 3H), 3.87 (s, 3H).

Example 5-13 Synthesis of2-(3-bromo-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 69)

A reaction time of 5.5 hours; a yield of 99%; ¹H NMR (400 MHz, DMSO-d₆)δ 10.95 (br s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.99 (br s, 1H), 7.79(br s, 1H), 7.57 (br s, 1H), 7.07 (br s, 1H); ¹³C NMR (100 MHz, DMSO-d₆)δ 168.5, 156.9, 153.2, 143.0, 139.6, 132.0, 128.3, 125.1, 124.2, 122.6,117.4, 115.0, 110.5.

Example 5-14 Synthesis of2-(3,5-dibromo-4-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid(Compound 70)

A reaction time of 4 hours; a yield of 87.7%; ¹H NMR (400 MHz, DMSO-d₆)δ 8.31 (s, 2H), 8.11 (s, 1H), 7.79 (d, 1H, J=8.0 Hz), 7.56 (d, 1H, J=8.0Hz); ¹³C NMR (100 MHz, DMSO-d6) δ 168.5, 155.2, 152.3, 143.1, 139.7,131.1, 125.2, 124.2, 122.3, 117.4, 115.0, 113.5

Example 6 Synthesis of Compounds 71 to 80

Table 6 below is provided herein to explain substitution patterns ofCompound 71 to 80, which are 2-(substituted phenyl)thiazolidinederivatives.

TABLE 6 Compound R¹ R² R³ R⁴ 71 H H OH H 72 H OH OH H 73 H OMe OH H 74 HOEt OH H 75 H OH OMe H 76 H H OMe H 77 H OMe OMe H 78 OMe H OMe H 79 HOMe OMe OMe 80 H OMe OH OMe

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 71 to 79 was performed as follows. In detail, ina DMF (5 mL) solvent, triethylamine (1.0 eq.) was added to a mixtureincluding substituted benzaldhehyde (300 mg) and cysteamine.HCl (1.5eq.), and then the reaction mixture was stirred at room temperature for2 to 4 hours. After water was added thereto, the reaction flask wasmaintained at a temperature of 0° C., and the produced precipitate wasfiltered and washed with iced water to obtain a target product. In thecase of Compound 79, after the reaction mixture was stirred, DMF wasevaporated therefrom under reduced pressure, and the residual wasdistributed between methylene chloride and NaHCO₃ aqueous solution. Anorganic layer was dried by using MgSO₄, filtered, and evaporated. Theresidual was purified by silica gel column chromatography using amixture including methylene chloride and methanol (60:1) as a developerto obtain a solid Compound 79

However, a synthesis method of Compound 80, which is slightly differentfrom the method described above, is separately described below.

Example 6-1 Synthesis of 4-(thiazolidin-2-yl)phenol (Compound 71)

A reaction time of 2 hours; a yield of 77.3%; ¹H NMR (500 MHz, DMSO-d₆)δ 9.40 (s, 1H), 7.25 (d, 2H, J=9.0 Hz), 6.69 (d, 2H, J=9.5 Hz), 5.33 (s,1H), 3.49 (br m, 1H), 3.06 (br s, 1H), 2.98-2.90 (m, 2H), 2.81 (br m,1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.5, 131.3, 129.1, 115.5, 73.9,53.4, 36.8.

Example 6-2 Synthesis of 4-(Thiazolidin-2-yl)benzene-1,2-diol (Compound72)

A reaction time of 3 hours; a yield of 11.8%; ¹H NMR (500 MHz, DMSO-d₆)δ 8.56 (s, 2H), 6.83 (s, 1H), 6.69 (d, 1H, J=8.0 Hz), 6.64 (d, 1H, J=8.0Hz), 5.26 (s, 1H), 3.46 (br m, 1H), 2.95 (br s, 1H), 2.96-2.87 (m, 2H),2.79 (br m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 145.6, 145.5, 131.9,118.8, 115.7, 115.4, 74.0, 53.3, 36.7.

Example 6-3 Synthesis of 2-methoxy-4-(thiazolidin-2-yl)phenol (Compound73)

A reaction time of 4 hours; a yield of 88.1%; ¹H NMR (500 MHz, DMSO-d₆)δ 8.91 (s, 1H), 6.89 (s, 1H), 6.83 (s, 2H), 5.32 (s, 1H), 3.73 (s, 3H),3.46 (br m, 1H), 3.04 (br s, 1H), 2.97-2.91 (m, 2H), 2.84 (br m, 1H);¹³C NMR (100 MHz, DMSO-d₆) δ 147.8, 146.8, 133.8, 118.6, 115.2, 112.4,73.7, 56.3, 53.3, 36.7.

Example 6-4 Synthesis of 2-ethoxy-4-(thiazolidin-2-yl)phenol (Compound74)

A reaction time of 3 hours; a yield of 87.2%; ¹H NMR (400 MHz, DMSO-d₆)δ 8.85 (s, 1H), 6.99 (s, 1H), 6.80 (d, 1H, J=8.0 Hz), 6.67 (d, 1H, J=8.0Hz), 5.28 (s, 1H), 3.96 (q, 2H, J=6.8 Hz), 3.47 (br m, 1H), 3.08 (br s,1H), 2.92-2.89 (m, 2H), 2.77 (br m, 1H), 1.28 (t, 3H, J=6.8 Hz); ¹³C NMR(100 MHz, DMSO-d₆) δ 147.1, 147.1, 131.8, 120.6, 115.6, 113.4, 74.1,64.5, 53.4, 36.8, 15.5.

Example 6-5 Synthesis of 2-methoxy-5-(thiazolidin-2-yl)phenol (Compound75)

A reaction time of 4 hours; a yield of 90.2%; ¹H NMR (500 MHz, DMSO-d₆)δ 8.94 (s, 1H), 7.04 (s, 1H), 6.84 (d, 1H, J=8.0 Hz), 6.69 (d, 1H, J=8.0Hz), 5.33 (s, 1H), 3.75 (s, 3H), 3.52 (br m, 1H), 3.11 (br s, 1H),2.99-2.92 (m, 2H), 2.81 (br m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ148.0,146.8, 131.9, 120.5, 115.6, 112.0, 74.1, 56.3, 53.4, 36.8.

Example 6-6 Synthesis of 2-(4-methoxyphenyl)thiazolidine (Compound 76)

A reaction time of 2 hours; a yield of 72.3%; ¹H NMR (500 MHz, CDCl₃) δ7.42 (d, 2H, J=7.0 Hz), 6.88 (d, 2H, J=7.0 Hz), 5.52 (s, 1H), 3.80 (s,3H), 3.64 (br m, 1H), 3.15-3.05 (m, 3H), 1.89 (br s, 1H); ¹³C NMR (100MHz, CDCl₃) δ159.7, 132.1, 128.7, 114.1, 73.3, 55.5, 53.0, 36.8.

Example 6-7 Synthesis of 2-(3,4-dimethoxyphenyl)thiazolidine (Compound77)

A reaction time of 3 hours; a yield of 74.9%; ¹H NMR (500 MHz, DMSO-d₆)δ 7.06 (s, 1H), 6.96 (d, 1H, J=8.0 Hz), 6.86 (d, 1H, J=8.0 Hz), 5.37 (s,1H), 3.73 (s, 3H), 3.72 (s, 3H), 3.50 (br m, 1H), 3.18 (br s, 1H),2.98-2.92 (m, 2H), 2.84 (br m, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 149.2,149.0, 133.5, 120.1, 112.0, 111.6, 73.9, 56.2, 56.1, 53.4, 36.8.

Example 6-8 Synthesis of 2-(2,4-dimethoxyphenyl)thiazolidine (Compound78)

A reaction time of 3 hours; a yield of 48%; ¹H NMR (500 MHz, CDCl₃) δ7.37 (d, 1H, J=9.5 Hz), 6.47 (s, 1H), 6.46 (d, 1H, J=9.5 Hz), 5.75 (s,1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.66 (br m, 1H), 3.10-2.99 (m, 3H),2.31 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 160.9, 158.5, 128.3, 120.5,104.4, 99.1, 68.7, 55.8, 55.6, 53.2, 36.4.

Example 6-9 Synthesis of 2-(3,4,5-trimethoxyphenyl)thiazolidine(Compound 79)

A reaction time of 3 hours; a yield of 95.6%; ¹H NMR (500 MHz, CD3OD-d4)δ 6.81 (s, 2H), 5.37 (s, 1H), 3.80 (s, 6H), 3.73 (s, 3H), 3.58 (br m,1H), 3.11-3.07 (m, 2H), 3.06 (m, 1H); ¹³C NMR (100 MHz, CD3OD-d4) δ153.3, 137.5, 135.7, 104.7, 72.6, 60.0, 55.5, 52.2, 35.5.

Example 6-10 Synthesis of 2,6-dimethoxy-4-(thiazolidin-2-yl)phenol(Compound 80)

In a solvent including an ethyl alcohol (2 mL) and water (2 mL), amixture including syringaldehyde (100 mg, 0.55 mmol), cysteamine.HCl(93.2 mg, 0.82 mmol), and sodium acetate (72 mg, 0.88 mmol) was stirredat room temperature for 4 hours. The produced precipitate was filteredand washed with water and methylene chloride to obtain a solid targetproduct Compound 80.

A reaction time of 4 hours; a yield of 44.4%; ¹H NMR (500 MHz, DMSO-d₆)δ 8.31 (s, 1H), 6.73 (s, 2H), 5.32 (d, 1H, J=11.5 Hz), 3.73 (s, 6H),3.51 (br m, 1H), 3.15 (m, 1H), 2.99-2.92 (m, 2H), 2.82 (m, 1H); ¹³C NMR(100 MHz, DMSO-d₆) δ148.3, 135.7, 131.0, 105.5, 74.4, 56.6, 53.4, 36.8.

Example 7 Synthesis of 4-(1,3-dithiolan-2-yl)phenol (Compound 81)

In a tetrahydrofuran (THF) (3 mL) solvent, boron trifluoride diethyletherate (0.03 mL, 0.25 mmol) was added to a mixed solution including4-hydroxybenzaldehyde (300 mg, 2.16 mmol) and 1,2-ethanedithiol (0.21mL, 2.46 mmol), and the reaction mixture was stirred at room temperaturefor 7 hours. The reaction mixture was distributed between methylenechloride and water, and an organic layer was dried by using MgSO4,filtered, and evaporated under reduced pressure to obtain Compound 81(465 mg, 95.3%).

A reaction time of 7 hours; a yield of 95.3%; ¹H NMR (500 MHz, CDCl₃) δ7.39 (d, 2H, J=8.5 Hz), 6.75 (d, 2H, J=9.0 Hz), 5.61 (s, 1H), 5.07 (brs, 1H), 3.48 (m, 2H), 3.33 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.6,132.2, 129.6, 115.5, 56.2, 40.4.

Example 8 Synthesis of Compounds 82 to 96

Table 7 below is provided to explain substitution patterns of Compounds82 to 93 and 95 and 96, which are 5-chloro-2-(substitutedphenyl)benzo[d]thiazole derivatives. Compound 94 has the followingdihydrobenzo[d]thiazol structure.

TABLE 7 Compound R¹ R² R³ R⁴ 82 H H OH H 83 H OH OH H 84 OH H OH H 85 HOMe OH H 86 H OEt OH H 87 H OH OMe H 88 H H OMe H 89 H OMe OMe H 90 H OHH OH 91 OMe H OMe H 92 OH H H H 93 H OMe OMe OMe 95 H Br OH H 96 H Br OHBr

OMe represents a methoxy group, and OEt represents an ethoxy group.

Synthesis of Compounds 82 to 89, and 91 to 94 was performed as follows.In detail, in a methyl alcohol (3 mL) solvent, a mixture of2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and substitutedbenzaldhehyde (1.5 eq.) was stirred at room temperature for 0.5 to 8hours. The reaction solvent was evaporated, and the resultant productwas solidified by using small amounts of methanol or a mixed solventincluding hexane and ethyl acetate or methylene chloride to obtain solidCompounds 82 to 89 and 91 to 94.

However, synthesis methods of Compounds 90, 95 and 96, which aredifferent from the method described above, were separately describedbelow.

Example 8-1 Synthesis of 4-(5-chlorobenzo[d]thiazol-2-yl)phenol(Compound 82)

Dark ochroid; a reaction time of 3 hours; a yield of 30.5%; a meltingpoint of 259.3 to 263.1° C. ¹H NMR (500 MHz, DMSO-d₆) δ 10.29 (s, 1H),8.10 (d, 1H, J=9.0 Hz), 8.02 (d, 1H, J=2.0 Hz), 7.91 (d, 2H, J=8.5 Hz),7.43 (d, 1H, J=9.0 Hz), 6.92 (d, 2H, J=8.5 Hz); ¹³C NMR (100 MHz,DMSO-d₆) δ 170.5, 161.5, 155.3, 133.5, 131.8, 129.9, 125.6, 124.3,124.2, 122.3, 116.8.

Example 8-2 Synthesis of4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,2-diol (Compound 83)

Beige solid; a reaction time of 10.5 hours; a yield of 33.5%; a meltingpoint of 127.4 to 129.1° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.78 (s, 1H),9.57 (s, 1H), 8.00-7.95 (m, 2H), 7.55 (s, 1H), 7.36-7.34 (m, 2H), 6.90(dd, 1H, J=2.5, 8.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.6, 155.3,150.1, 146.5, 133.5, 131.8, 125.4, 124.7, 124.0, 122.3, 120.4, 116.8,114.7.

Example 8-3 Synthesis of4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 84)

Lemon-colored solid; a reaction time of 2.7 hours; a yield of 36.3%; amelting point of 277.9 to 280.1° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 11.43(s, 1H), 10.17 (s, 1H) 8.03 (d, 1H, J=8.8 Hz), 7.97 (d, 1H, J=2.0 Hz),7.94 (d, 1H, J=9.2 Hz), 7.35 (dd, 1H, J=2.0, 8.4 Hz), 6.42 (s, 1H), 6.41(d, 1H, J=8.8 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 168.2, 162.5, 158.9,153.3, 133.3, 131.6, 130.7, 124.9, 123.9, 121.5, 111.1, 109.2, 103.2.

Example 8-4 Synthesis of 4-(5-chlorobenzo[d]thiazol-2-yl (Compound 85)

Light brown solid; a reaction time of 30

; a yield of 14.7%; a melting point of 173.4 175.4° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.93 (s, 1H), 8.10 (d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=2.0 Hz),7.59 (d, 1H, J=2.0 Hz), 7.50 (dd, 1H, J=2.0, 8.0 Hz), 7.44 (dd, 1H,J=2.0, 8.5 Hz), 6.93 (d, 1H, J=8.0 Hz), 3.88 (s, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 170.6, 155.3, 151.1, 148.8, 133.6, 131.8, 125.7, 124.7,124.3, 122.4, 122.2, 116.6, 110.8, 56.4.

Example 8-5 Synthesis of 4-(5-chlorobenzo[d]thiazol-2-yl)-2-ethoxyphenol(Compound 86)

White solid; a reaction time of 10.5 hours; a yield of 20.2%; a meltingpoint of 102.1 to 103.4° C. ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H),7.99 (d, 1H, J=8.8 Hz), 7.96 (d, 1H, J=2.0 Hz), 7.52 (d, 1H, J=2.0 Hz),7.42 (dd, 1H, J=2.0, 8.0 Hz), 7.35 (dd, 1H, J=2.4, 8.8 Hz), 6.91 (d, 1H,J=8.8 Hz), 4.07 (q, 2H, J=6.8 Hz), 1.33 (t, 3H, J=6.8 Hz); ¹³C NMR (100MHz, DMSO-d₆) δ 170.5, 155.2, 151.3, 147.9, 133.6, 131.8, 125.5, 124.6,124.0, 122.3, 122.1, 116.7, 112.0, 64.7, 15.3.

Example 8-6 Synthesis of5-(5-chlorobenzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 87)

White solid; a reaction time of 4 hours; a yield of 24.1%; a meltingpoint of 158.2 to 158.6° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H),8.07 (d, 1H, J=8.8 Hz), 8.02 (d, 1H, J=2.0 Hz), 7.49 (d, 1H, J=2.4 Hz),7.46 (dd, 1H, J=2.4, 8.4 Hz), 7.41 (dd, 1H, J=2.0, 8.4 Hz), 7.04 (d, 1H,J=8.8 Hz), 3.81 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.3, 155.3,151.6, 147.7, 133.7, 131.9, 125.9, 125.7, 124.3, 122.5, 120.0, 114.3,113.0, 56.4.

Example 8-7 Synthesis of 5-chloro-2-(4-methoxyphenyl)benzo[d]thiazole(Compound 88)

Brownish gold-colored crystal; a reaction time of 30 min; a yield of20.2%; a melting point of 150.3 to 151.0° C.; ¹H NMR (400 MHz, DMSO-d₆)δ 8.08 (d, 1H, J=8.4 Hz), 8.01 (d, 1H, J=2.0 Hz), 7.97 (d, 2H, J=8.8Hz), 7.40 (dd, 1H, J=2.0, 8.8 Hz), 7.06 (d, 2H, J=8.8 Hz), 3.97 (s, 3H);¹³C NMR (100 MHz, DMSO-d₆) δ170.1, 162.8, 155.3, 133.7, 131.9, 129.7,125.8, 124.5, 124.4, 122.5, 115.5, 56.2.

Example 8-8 Synthesis of5-chloro-2-(3,4-dimethoxyphenyl)benzo[d]thiazole (Compound 89)

White solid; a reaction time of 5 hours; a yield of 19.1%; a meltingpoint of 165.2 to 167.1° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (d, 1H,J=8.5 Hz), 8.08 (s, 1H), 7.61 (d, 1H, J=7.5 Hz), 7.60 (s, 1H), 7.46 (d,1H, J=8.5 Hz), 7.12 (d, 1H, J=7.5 Hz), 3.87 (s, 3H), 3.84 (s, 3H); ¹³CNMR (100 MHz, DMSO-d₆) δ 170.3, 155.2, 152.6, 149.8, 133.7, 131.9,125.9, 125.9, 124.3, 122.5, 121.8, 112.6, 110.1, 56.4, 56.3.

Example 8-9 Synthesis of5-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 90)

In an acetic acid (0.6 mL) solvent, a mixture including2-amino-4-chlorobenzenethiol (100 mg, 0.44 mmol),3,5-dihydroxybenzaldehyde (60 mg, 0.44 mmol), and sodium acetate (107mg, 1.30 mmol) was refluxed for 7 hours. After cooling, the reactionmixture was distributed between ethyl acetate and water, and an organiclayer was dried by using MgSO₄, filtered, and evaporated under reducedpressure. The residual was purified by silica gel column chromatographyusing hexane and ethyl acetate (2:1) as a developer to obtain a solidCompound 90 (64.2 mg, 34.7%).

Light chololet-color; a reaction time of 7 hours; a yield of 34.7%; amelting point of 129.6 to 130.6° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74(s, 2H), 8.11 (d, 1H, J=8.4 Hz), 8.07 (d, 1H, J=2.0 Hz), 7.45 (dd, 1H,J=2.4, 8.4 Hz), 6.93 (d, 2H, J=2.0 Hz), 6.38 (d, 1H, J=2.4 Hz); ¹³C NMR(100 MHz, DMSO-d₆) δ 170.6, 159.8, 155.0, 134.7, 133.7, 132.0, 126.2,124.4, 122.9, 106.5, 105.9.

Example 8-10 Synthesis of5-chloro-2-(2,4-dimethoxyphenyl)benzo[d]thiazole (Compound 91)

Bluish green; a reaction time of 6 hours; a yield of 11.2%; a meltingpoint of 138.6 to 140.3° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (d, 1H,J=8.8 Hz), 8.06 (d, 1H, J=8.4 Hz), 7.99 (d, 1H, J=1.6 Hz), 7.37 (dd, 1H,J=2.0, 8.4 Hz), 6.77 (d, 1H, J=2.0 Hz), 6.72 (dd, 1H, J=2.0, 8.8 Hz),4.01 (s, 3H), 3.84 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 165.2, 163.9,159.3, 153.3, 134.3, 131.5, 130.7, 125.1, 123.8, 121.9, 114.6, 107.8,99.2, 56.8, 56.4.

Example 8-11 Synthesis of 2-(5-chlorobenzo[d]thiazol-2-yl)phenol(Compound 92)

Shining white solid; a reaction time of 8 hours; a yield of 8.4%; amelting point of 194.2 to 195.7° C.; ¹H NMR (400 MHz, CDCl₃) δ 12.22 (s,1H), 7.96 (s, 1H), 7.79 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=8.0 Hz),7.44-7.35 (m, 2H), 7.09 (d, 1H, J=8.4 Hz), 6.95 (t, 1H, J=7.6 Hz); ¹³CNMR (100 MHz, CDCl3) δ 171.4, 158.2, 153.0, 133.4, 133.0, 131.1, 128.7,126.2, 122.4, 122.2, 119.9, 118.2, 116.7.

Example 8-12 Synthesis of5-chloro-2-(3,4,5-trimethoxyphenyl)benzo[d]thiazole (Compound 93)

White solid; a reaction time of 7 hours; a yield of 29.0%; a meltingpoint of 159.4 to 160.0° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.15 (d, 1H,J=9.0 Hz), 8.12 (d, 1H, J=2.0 Hz), 7.49 (dd, 1H, J=2.0, 8.5 Hz), 7.31(s, 2H), 3.90 (s, 6H), 3.75 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ 170.2,155.1, 154.1, 141.3, 134.0, 132.1, 128.6, 126.2, 124.4, 122.8, 105.3,60.9, 56.9.

Example 8-13 Synthesis of4-(5-chloro-2,3-dihydrobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol(Compound 94)

White solid; a reaction time of 6 hours; a yield of 17.2%; a meltingpoint of 155.8 to 158.6° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s, 1H),7.16 (s, 1H), 6.94 (d, 1H, J=8.0 Hz), 6.78 (s, 2H), 6.56 (dd, 1H, J=2.0,8.0 Hz), 6.51 (d, 1H, J=2.0 Hz), 6.47 (s, 1H), 3.92 (s, 6H); ¹³C NMR(100 MHz, DMSO-d₆) δ 149.8, 148.5, 136.5, 132.3, 130.3, 124.8, 122.5,118.2, 108.0, 104.7, 71.1, 56.7.

Example 8-14 Synthesis of 2-bromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol(Compound 95)

In a dimethyl sulfoxide (DMSO) (2 mL) solvent, a solution including3-bromo-4-hydroxybenzaldehyde (163.7 mg, 0.81 mmol) and2-amino-4-chlorobenzenethiol (100 mg, 0.45 mmol) was refluxed for 1hour. After cooling, the residual was distributed between ethyl acetateand water, and an organic layer was dried by using MgSO₄, filtered, andevaporated under reduced pressure. The resultant residual was added towater, and then, the precipitate was filtered and the filtered productwas washed with water and methylene chloride to obtain a solid Compound95 (46.4 mg, 17.6%).

Blueish green solid; a reaction time of 1 hours; a yield of 17.6%; amelting point of 226.0 to 228.1° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 11.11(s, 1H), 8.11 (d, 1H, J=1.2 Hz), 8.04 (d, 1H, J=8.8 Hz), 7.97 (d, 1H,J=1.2 Hz), 7.82 (dd, 1H, J=1.6, 8.4 Hz), 7.38 (dd, 1H, J=1.2, 8.8 Hz),7.06 (d, 1H, J=8.4 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 168.8, 158.0,155.1, 133.7, 132.1, 132.0, 128.9, 125.8, 125.7, 124.2, 122.5, 117.5,110.9.

Example 8-15 Synthesis of2,6-dibromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 96)

In a DMF (3 mL) solvent, a solution including2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and3,5-dibromo-4-hydroxybenzaldehyde (127 mg, 0.63 mmol) was heated at atemperature of 100° C. for 8.5 hours. After DMF was evaporatedtherefrom, the residual was purified by silica gel column chromatographyusing hexane and ethyl acetate (5:1) as a developer to obtain a solidCompound 96 (34.3 mg, 18.1%).

A reaction time of 8.5 hours; a yield of 18.1%; ¹H NMR (400 MHz,DMSO-d₆) δ 10.85 (s, 1H), 8.16 (m, 3H), 8.08 (br s, 1H), 7.47 (br s, 1H)¹³C NMR (100 MHz, DMSO-d₆) δ 167.3, 154.9, 154.5, 134.0, 132.2, 131.6,127.3, 126.3, 124.6, 122.8, 113.1

Example 9 Synthesis of Compounds 97a to 97d

Example 9-1 Synthesis of ethyl 2-(4-formylphenoxy)-2-methylpropanoate(Compound 97a)

In an ethanol solvent, 1 N ethoxy sodium (NaOEt) (1.1 eq.) was addeddropwise to 4-hydroxybenzaldehyde (1.0 eq.) and ethyl α-bromoisobutyrate(1.1 eq.), and the reaction mixture was refluxed. After the ethanol wasevaporated, the residual was distributed between ethyl acetate andwater, and an organic layer was dried by using MgSO₄, filtered, andevaporated. The residual was purified by silica gel columnchromatography using hexane and ethyl acetate (8:1) to obtain Compound97a.

A reaction time of 12.5 hours; a yield of 41.9%; ¹H NMR (400 MHz,DMSO-d₆) δ 9.70 (s, 1H), 7.62 (d, 2H, J=8.8 Hz), 6.73 (d, 2H, J=8.8 Hz),4.05 (q, 2H, J=6.8 Hz), 1.50 (s, 6H), 1.03 (t, 3H, J=7.2 Hz); ¹³C NMR(100 MHz, DMSO-d₆) δ 190.7, 173.4, 161.0, 131.6, 130.4, 117.8, 79.6,61.7, 25.4, 14.0.

Example 9-2 Synthesis of ethyl 2-(3-formylphenoxy)-2-methylpropanoate(Compound 97b)

In an ethanol solvent, 1 N ethoxy sodium (NaOEt) (1.1 eq.) was addeddropwise to 3-hydroxybenzaldehyde (1.0 eq.) and ethyl α-bromoisobutyrate(1.1 eq.), and the reaction mixture was refluxed. After the ethanol wasevaporated, the residual was distributed between ethyl acetate andwater, and an organic layer was dried by using MgSO₄, filtered, andevaporated. The residual was purified by silica gel columnchromatography using hexane and ethyl acetate (8:1) to obtain Compound97b.

A reaction time of 22 hours; a yield of 59.0%; ¹H NMR (400 MHz, DMSO-d₆)δ 9.92 (s, 1H), 7.52 (dd, 1H, J=1.2, 7.2 Hz), 7.47 (t, 1H, J=8.0 Hz),7.23 (m, 1H), 7.11 (m, 1H), 4.13 (q, 2H, J=7.2 Hz), 1.52 (s, 6H), 1.11(t, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 193.3, 173.5, 156.3,138.1, 130.9, 125.6, 124.4, 118.1, 79.7, 61.8, 25.5, 14.4.

Example 9-3 Synthesis of ethyl 2-(4-formylphenoxy)-2-methylpropanoicacid (Compound 97c)

The obtained Compound 97a (1.0 eq.) was dissolved in 1,4-dioxane, and 1N NaOH (1.4 eq.) was added thereto. The reaction mixture was stirred atroom temperature, and after a volatile material was evaporated, theresidual was distributed between methylene chloride and water. An waterlayer was acidified by using a 12 N HCl and extracted by using methylenechloride. An organic layer was evaporated to obtain Compound 97c.

A reaction time of 4 hours; a yield of 99%; ¹H NMR (500 MHz, DMSO-d₆) δ10.54 (s, 1H), 9.83 (s, 1H), 7.79 (dd, 2H, J=9.0 Hz), 6.95 (d, 2H, J=8.5Hz), 1.69 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ 191.7, 178.5, 161.0,132.0, 130.5, 118.5, 79.5, 25.5.

Example 9-4 Synthesis of 2-(3-formylphenoxy)-2-methylpropanoic acid(Compound 97d)

The obtained Compound 97b (1.0 eq.) was dissolved in 1,4-dioxane, and 1N NaOH (1.4 eq.) was added thereto. The reaction mixture was stirred atroom temperature, and after a volatile material was evaporated, theresidual was distributed between methylene chloride and water. Anaqueous layer was acidified by using a 12 N HCl and extracted by usingmethylene chloride. An organic layer was evaporated to obtain Compound97d.

A reaction time of 7.5 hours; a yield of 95.0%; ¹H NMR (400 MHz,DMSO-d₆) δ 9.91 (s, 1H), 7.52 (d, 1H, J=7.2 Hz), 7.41 (t, 1H, J=8.0 Hz),7.38 (br s, 1H), 7.18 (dd, 1H, J=1.6, 8.0 Hz), 1.63 (s, 6H); ¹³C NMR(100 MHz, DMSO-d₆) δ 192.4, 179.1, 155.9, 137.8, 130.2, 126.4, 124.9,119.8, 79.7, 25.4.

Example 10 Synthesis of Compounds 97 to 106

Example 10-1 Synthesis of2-(4-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound 97)

In a methanol solvent, a solution including Compound 97c (1.0 eq.) and2-aminothiophenol (1.0 eq.) was stirred at room temperature. Aftermethanol was removed, the precipitate was filtered, and washed with coldmethanol to obtain a solid target product.

White solid; a reaction time of 17 hours; a yield of 40.3%; a meltingpoint of 200.3 to 201.5° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, 1H,J=8.0 Hz), 7.98-7.95 (m, 3H), 7.47 (td, 1H, J=1.2, 8.4 Hz), 7.38 (td,1H, J=1.2, 8.4 Hz), 6.94 (d, 2H, J=8.8 Hz), 1.56 (s, 6H); ¹³C NMR (100MHz, DMSO-d₆) δ 175.3, 167.6, 158.8, 154.3, 135.0, 129.3, 127.2, 126.7,125.8, 123.2, 122.9, 118.9, 79.5, 25.8.

Example 10-2 Synthesis of2-methyl-2-(4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenoxy)propanoicacid (Compound 98)

A solution including Compound 97c (1.0 eq.) and2-amino-4-trifluoromethylbenzenethiol (1.0 eq.) was stirred in amethanol solvent at room temperature. After methanol was removed, theprecipitate was filtered, and washed with cold methanol to obtain asolid target product.

White solid; a reaction time of 4 hours; a yield of 31.5% melting point,97.3 to 98.5° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, 1H, J=0.8 Hz), 7.94(d, 2H, J=8.8 Hz), 7.90 (dd, 1H, J=0.8, 8.4 Hz), 7.53 (dd, 1H, J=1.2,8.4 Hz), 6.88 (d, 2H, J=9.2 Hz), 1.65 (s, 6H); ¹³C NMR (100 MHz, CDCl₃)δ 174.5, 169.8, 158.7, 154.0, 138.5, 129.2, 129.1 (q, J=32.6 Hz), 126.9,124.5 (q, J=270.9 Hz), 122.3, 121.4, 120.2, 118.8, 79.7, 25.6.

Example 10-3 Synthesis of2-(4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid(Compound 99)

In an acetic acid (0.37 mL) solvent, a mixture including Compound 97c(78.2 mg, 0.38 mmol), 2-amino-4-chlorobenzenethiol (60.0 mg, 0.38 mmol),and sodium acetate (NaOAc) (93.6 mg, 1.13 mmol) was refluxed for 1 hour.After cooling, the reaction mixture was distributed between ethylacetate and water, and an organic layer was evaporated under reducedpressure. The produced precipitate was filtered, and washed withmethylene chloride to obtain Compound 99 (46.6 mg, 39.6%).

White solid; a reaction time of 1 hours; a yield of 39.6%; a meltingpoint of 190.8 to 192.0° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, 1H,J=8.4 Hz), 7.98 (d, 1H, J=2.0 Hz), 7.92 (d, 2H, J=8.8 Hz), 7.37 (dd, 1H,J=2.0, 8.8 Hz), 6.92 (d, 2H, J=8.8 Hz), 1.55 (s, 6H); ¹³C NMR (100 MHz,DMSO-d₆) δ 175.2, 169.8, 159.0, 155.2, 133.7, 131.9, 129.4, 126.3,125.8, 124.2, 122.5, 118.9, 79.5, 25.8.

Example 10-4 Synthesis of7,8-bis(tert-butyldimethylsilyloxy)-4-phenyl-2H-chromen-2-one (Compound100)

In a methylene chloride (4 mL) solvent, tert-butyldimethylsilylchloride(TBSCl) (144.6 mg, 0.96 mmol) was added to a solution including7,8-dihydroxy-4-phenylcoumarin (81.3 mg, 0.32 mmol) and imidazole (130.6mg, 1.92 mmol), and the reaction mixture was stirred at room temperaturefor 6 hours. The reaction mixture was distributed between methylenechloride and water, and an organic layer was evaporated under reducedpressure, filtered, and evaporated. The residual was purified by silicagel column chromatography using hexane and ethyl acetate (15:1) toobtain Compound 100 (149.6 mg, 97%).

¹H NMR (400 MHz, CDCl₃) δ 7.43 (m, 5H), 6.93 (d, 1H, J=8.8 Hz), 6.73 (d,1H, J=8.8 Hz), 6.17 (s, 1H), 1.08 (s, 9H), 0.98 (s, 9H), 0.29 (s, 6H),0.25 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 160.6, 156.1, 150.7, 147.6,136.0, 135.2, 129.7, 128.9, 128.7, 119.0, 116.9, 114.1, 112.4, 26.2,18.9, 18.9, −3.5.

Example 10-5 Synthesis of 2-(2,4-dihydroxyphenyl)thiazole-4-carboxylicacid](Compound 101)

1) Synthesis of 2,4-dihydroxybenzonitrile (Compound 101a)

In an acetic acid (10 mL) solvent, a solution including2,3-dihydroxybenzaldehyde (3.0 g, 21.7 mmol), sodium acetate (NaOAc)(3.54 g, 43.4 mmol), and nitroethane (3.24 g, 43.4 mmol) was refluxedfor 8 hours. After cooling, the reaction mixture was distributed betweenethyl acetate and water. Until a pH of the residual aqueous layerreached 8, an organic layer was washed with a saturated NaHCO₃ solution.The organic layer was evaporated, the residual was purified by silicagel column chromatography using hexane and ethyl acetate (2:1) as adeveloper to obtain Compound 101a (1.88 g, 59%).

A melting point of 183 to 186° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (brs, 1H), 10.33 (br s, 1H), 7.33 (d, 1H, J=8.4 Hz), 6.38 (d, 1H, J=2.0Hz), 6.28 (dd, 1H, J=2.0, 8.4 Hz).

2) Synthesis of 2-(2,4-dihydroxyphenyl)-4,5-dihydrothiazole-4-carboxylicacid] (Compound 101b)

In a mixed solvent including methanol (30 mL) and phosphate buffersolution (20 mL), NaHCO₃ (466 mg, 5.55 mmol) was carefully added to asolution including the obtained Compound 101a (0.5 g, 3.70 mmol) andL-cysteine hydrochloride monohydrate (974 mg, 5.55 mmol), and thereaction mixture was refluxed for 10 hours. After methanol wasevaporated, the reaction mixture was acidified by using 1 N HCl toincrease a pH to 2. The resultant precipitate was filtered, and washedwith water to obtain Compound 101b (613 mg, 69%).

A melting point of 269 to 270° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 10.25 (brs, 1H), 7.21 (d, 1H, J=8.4 Hz), 6.34 (d, 1H, J=8.8 Hz), 6.27 (s, 1H),5.34 (t, 1H, J=6.8 Hz), 3.64-3.51 (m, 2H).

3) Synthesis of 2-(2,4-Dihydroxyphenyl)thiazole-4-carboxylic acid(Compound 101)

In a DMF (5 mL) solvent, a suspension of Compound 101b (100 mg, 0.41mmol) and MnO₂ (640 mg, 6.26 mmol) was stirred at room temperature for24 hours. After DMF was evaporated, 1 N a NaOH solution (0.5 mL) wasadded to the residual. The reaction mixture was filtered, washed withwater, and the filtrate was acidified by using 1 N HCl to increase a pHto 2. The produced precipitate was filtered, and washed with cold waterto obtain Compound 101 (46.2 mg, 43%).

1H NMR (400 MHz, DMSO-d₆) δ 11.22 (s, 1H), 9.97 (s, 1H), 8.29 (s, 1H),7.87 (d, 1H, J=8.8 Hz), 6.40 (s, 1H), 6.38 (d, 1H, J=9.2 Hz).

Example 10-6 Synthesis of(4R)-2-(3,4-dihydroxyphenyl)-4,5-dihydrothiazole-4-carboxylic acid(Compound 102)

Compound 102 was synthesized in such a manner that is similar to thatused in synthesizing Compound 101b.

A reaction time of 12 hours; a yield of 20%; a melting point of 178-179°C.; ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (d, 1H, J=2.0 Hz), 7.00 (dd, 1H,J=2.0, 8.4 Hz), 6.74 (d, 1H, J=8.4 Hz), 4.96 (t, 1H, J=8.8 Hz), 3.49 (d,2H, J=9.2 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 173.3, 167.5, 149.6, 145.9,124.7, 121.3, 116.1, 115.7, 79.9, 35.7.

Example 10-7 Synthesis of Compounds 103 to 105

1) Synthesis of (2R/S,4R)-methyl2-(3,4-dihydroxyphenyl)thiazolidine-4-carboxylate (Compound 104)

In a co-solvent of ethanol (5 mL) and water (5 mL), a solution includingNaHCO₃ (486 mg, 5.79 mmol), 3,4-dihydroxybenzaldhehyde(3,4-dihydroxybenzaldehyde) (800 mg, 5.80 mmol), and L-cysteine methylester hydrochloride (1.0 g, 5.84 mmol) was stirred at room temperaturefor 5 hours. After ethanol was evaporated, the reaction mixture wasdistributed between ethyl acetate and water, and an organic layer wasdried, filtered, and evaporated. The residual was purified by silica gelcolumn chromatography using hexane and ethyl acetate (4:1) to obtain asolid Compound 104 (1.23 g, 83%).

A melting point of 116 to 118° C.; ¹H NMR (400 MHz, CD₃OD) δ 6.96-6.93(m, 2H), 6.85-6.80 (m, 2H), 6.73 (d, 1H, J=8.4 Hz), 6.71 (d, 1H, J=8.0Hz), 5.49 (s, 1H), 5.34 (s, 1H), 4.39 (dd, 1H, J=3.6, 7.2 Hz), 3.96 (t,1H, J=8.4 Hz), 3.76 (s, 3H), 3.73 (s, 3H), 3.39 (dd, 1H, J=7.2, 10.4Hz), 3.36 (dd, 1H, J=7.2, 10.8 Hz), 3.26 (dd, 1H, J=3.6, 10.8 Hz), 3.11(dd, 1H, J=8.4, 10.0 Hz); ¹³C NMR (100 MHz, CD₃OD) δ 172.7, 171.9,145.7, 145.6, 145.3, 145.1, 131.2, 129.5, 119.0, 118.9, 115.1, 114.9,114.5, 114.3, 71.7, 71.0, 65.0, 64.6, 51.9, 51.7, 38.0, 37.3.

2) Synthesis of4-((2R/S,4R)-4-(methoxycarbonyl)thiazolidin-2-yl)-1,2-phenylenediacetate (Compound 105)

In a methylene chloride (75 mL) solvent, an anhydrous acetic acid (0.89mL, 9.60 mmol) was added dropwise to a solution including Compound 104(1.23 g, 4.83 mmol) and triethylamine (Et₃N) (1.35 mL, 9.62 mmol), andthe reaction mixture was stirred at room temperature for 4 hours. Aftervolatile materials evaporate, the residual was distributed between ethylacetate and water, and an organic layer was dried, filtered, andevaporated. The residual was purified by silica gel columnchromatography using hexane and ethyl acetate (4:1) to obtain a solidCompound 105 (1.214 g, 75.1%).

¹H NMR (500 MHz, CDCl₃) δ 7.44-7.37 (m, 4H), 7.20 (d, 1H, J=8.0 Hz),7.14 (d, 1H, J=8.5 Hz), 5.82 (s, 1H), 5.54 (s, 1H), 4.10 (t, 1H, J=7.0Hz), 3.98 (dd, 1H, J=7.5, 8.5 Hz), 3.80 (s, 3H), 3.79 (s, 3H), 3.45 (dd,1H, J=7.0, 10.0 Hz), 3.36 (dd, 1H, J=7.0, 10.5 Hz), 3.14 (dd, 1H, J=6.5,10.5 Hz), 3.09 (dd, 1H, J=9.5, 10.5 Hz), 2.30 (s, 3H), 2.29 (s, 3H),2.28 (s, 3H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.3, 171.6,168.4, 168.4, 168.3, 168.3, 142.4, 142.3, 142.0, 141.7, 140.8, 137.3,126.1, 125.5, 124.6, 124.5, 123.8, 123.4, 123.0, 122.3, 71.8, 69.9,65.7, 64.2, 52.8, 52.8, 39.3, 38.2, 20.9, 20.8.

3) Synthesis of 4-(4-(Methoxycarbonyl)thiazol-2-yl)-1,2-phenylenediacetate (Compound 103)

In a CCl₄ (5 mL) solvent, NBS (N-bromosuccinimide) (10.6 mg, 0.06 mmol)and AIBN (2,2′-azobis(2-methylpropionitrile)) (3.0 mg) were added to asolution of Compound 105 (11.2 mg, 0.03 mmol), and the reaction mixturewas refluxed for 5 hours. After volatile materials evaporate, theresidual was distributed between ethyl acetate and water, and an organiclayer was dried, filtered, and evaporated. The residual was purified bysilica gel column chromatography using hexane and ethyl acetate (4:1) toobtain a solid Compound 103 (3.0 mg, 33%).

A melting point of 137 to 138° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.19 (s,1H), 7.90 (d, 1H, J=2.5 Hz), 7.87 (dd, 1H, J=2.0, 8.5 Hz), 7.31 (d, 1H,J=8.5 Hz), 3.98 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 168.2, 168.1, 167.1, 162.0, 148.1, 144.3, 142.8, 131.6, 127.9,125.3, 124.3, 122.3, 52.8, 20.9, 20.8.

Example 10-8 Synthesis of3,6-bis((oxiran-2-yl)methoxy)-2-phenyl-4H-chromen-4-one (Compound 106)

In a DMF (4 mL) solvent, potassium carbonate (180.2 mg, 1.30 mmol) andepichlorohydrin (0.2 mL, 2.17 mmol) were added to a3,6-dihydroxyflavone(3,6-dihydroxyflavone) (110.5 mg, 0.43 mmol)solution. After stirring at a temperature of 70° C. for 8 hours, anammonium chloride aqueous solution was added to the reaction mixture.The reaction mixture was distributed between diethyl ether and water,and an organic layer was dried by using anhydrous MgSO₄, filtered, andevaporated under reduced pressure. The residual was purified by silicagel column chromatography using hexane and ethyl acetate (1:1.5) as adeveloper to obtain Compound 106 (25.3 mg, 16%) that is a white solidbis-oxyranyl flavone.

A reaction time of 8 hours; a yield of 16%; a melting point of 90.6 to91.1° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.13-8.11 (m, 2H), 7.59 (d, 1H,J=3.0 Hz), 7.55-7.51 (m, 3H), 7.50 (d, 1H, J=9.0 Hz), 7.34 (dd, 1H,J=3.0, 9.5 Hz), 4.43-4.39 (m, 2H), 4.03-3.98 (m, 2H), 3.43-3.40 (m, 1H),3.28-3.26 (m, 1H), 2.94 (t, 1H, J=4.5 Hz), 2.80 (dd, 1H, J=2.5, 4.5 Hz),2.76 (t, 1H, J=4.5 Hz), 2.58 (dd, 1H, J=2.5, 5.0 Hz); ¹³C NMR (100 MHz,CDCl₃) δ 174.78, 156.04, 155.75, 150.68, 140.03, 131.07, 128.95, 128.71,124.87, 124.51, 119.92, 105.60, 87.13, 73.69, 69.60, 50.66, 50.13,44.74, 44.61; LRMS(FAB+) m/z 367 (M+H)⁺; HRMS(FAB+) m/z C₂₁H₁₉O₆ (M+H)⁺calcd 367.1182. obsd 367.1184.

Example 11 Synthesis of Compounds 107 to 112

1) Synthesis of 4-(benzyloxy)benzaldehyde (Compound 107a)

In an acetonitrile (30 mL) solvent, benzyl bromide (1.95 mL, 16.40 mmol)was added to a solution including 4-hydroxybenzaldhehyde (2.0 g, 16.38mmol) and potassium carbonate (3.40 g, 24.60 mmol), and then, thereaction mixture was refluxed for 1.5 hours. After cooling, the reactionmixture was distributed between methylene chloride and water. An organiclayer was dried by using MgSO₄, and filtered. A filtrate was evaporated,and water was added to the resultant solid. The solid was filtered andwashed with water to obtain 4-(benzyloxy)benzaldehyde (3.082 g, 88.7%).

1H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 7.82 (d, 2H, J=9.2 Hz),7.43-7.34 (m, 5H), 7.06 (d, 2H, J=8.8 Hz), 5.14 (s, 2H); ¹³C NMR (100MHz, CDCl₃) δ 191.0, 164.0, 136.1, 132.2, 130.3, 129.0, 128.6, 127.7,115.4, 70.5.

2) Synthesis of 3-(benzyloxy)benzaldehyde (Compound 107b)

In an acetonitrile (50 mL) solvent, benzyl bromide (4.6 mL, 38.68 mmol)was added to a solution including 3-hydroxybenzaldehyde (5.0 g, 40.94mmol) and potassium carbonate (8.49 g, 61.43 mmol), and the reactionmixture was refluxed for 3 hours. After cooling, the reaction mixturewas distributed between methylene chloride and water. An organic layerwas dried by using MgSO₄, and filtered. A filtrate was evaporated, andwater was added to the resultant solid. The solid was filtered andwashed with water to obtain Compound 107b.

¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.54-7.51 (m, 3H), 7.47 (d,2H, J=7.5 Hz), 7.40 (t, 2H, J=7.0 Hz), 7.37-7.32 (m, 2H), 5.19 (s, 2H);¹³C NMR (100 MHz, DMSO-d₆) δ 193.6, 159.5, 138.3, 137.3, 131.1, 129.1,128.6, 128.4, 123.4, 122.4, 114.6, 70.1.

3) Synthesis of Compounds 107 to 112

In a methanol solvent, a solution including Compound 107a (1.0 eq.) orCompound 107b (1.0 eq.) and 2-aminothiophenol analog (1.0 eq.) wasstirred at room temperature. After methanol was removed, the producedprecipitate was filtered and the resultant product was washed with coldmethanol to obtain solid Compounds 108 through 111. In the case ofCompounds 107 and 112, silica gel column chromatography using hexane andethyl acetate (20:1) were performed thereon for the purification toobtain solid Compound 107 and Compound 112

Example 11-1 Synthesis of 2-(4-(benzyloxy)phenyl)benzo[d]thiazole(Compound 107)

Yellowish white; a reaction time of 16 hours; a yield of 19.3%; amelting point of 166.1 to 167.2° C.; ¹H NMR (400 MHz, DMSO-d₆) δ8.08-7.96 (m, 4H), 7.48-7.24 (m, 7H), 7.16 (d, 2H, J=7.6 Hz), 5.18 (s,2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.7, 161.5, 154.3, 137.3, 134.9,129.6, 129.2, 128.7, 128.5, 127.2, 126.4, 125.8, 123.1, 122.9, 116.3,70.2.

Example 11-2 Synthesis of2-(4-(benzyloxy)phenyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound108)

White solid; a reaction time of 19 hours; a yield of 57.7%; a meltingpoint of 194.3 to 195.1° C.; ¹H NMR (500 MHz, CDCl₃) δ 8.29 (s, 1H),8.05 (d, 2H, J=8.5 Hz), 7.98 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.0 Hz),7.47 (d, 2H, J=7.0 Hz), 7.42 (t, 2H, J=7.5 Hz), 7.36 (t, 1H, J=7.5 Hz),7.10 (d, 2H, J=9.0 Hz), 5.17 (s, 2H).

Example 11-3 Synthesis of2-(4-(benzyloxy)phenyl)-5-chlorobenzo[d]thiazole (Compound 109)

Green solid; a reaction time of 4 hours; a yield of 49.8%; a meltingpoint of 142.7 to 143.3° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H),7.89 (d, 2H, J=8.4 Hz), 7.51 (d, 1H, J=8.4 Hz), 7.44 (d, 2H, J=7.2 Hz),7.39 (t, 2H, J=7.2 Hz), 7.33 (t, 1H, J=6.8 Hz), 7.06 (d, 2H, J=8.8 Hz),7.00 (d, 1H, J=2.4 Hz), 5.13 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 162.2,160.4, 150.3, 136.5, 133.0, 131.4, 130.5, 129.1, 128.9, 128.4, 127.7,127.6, 126.4, 117.7, 115.4, 70.4.

Example 11-4 Synthesis of 2-(3-(benzyloxy)phenyl)benzo[d]thiazole(Compound 110)

Ivory; a reaction time of 2 hours; a yield of 30.4%; a melting point of121.5 to 122.1° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.08 (dd, 1H, J=1.2, 8.0Hz), 7.89 (dd, 1H, J=1.2, 8.0 Hz), 7.77 (t, 1H, J=2.0 Hz), 7.66 (ddd,1H, J=1.0, 2.0, 7.6 Hz), 7.51-7.45 (m, 3H), 7.43-7.34 (m, 5H), 7.10(ddd, 1H, J=1.2, 2.8, 8.4 Hz), 5.16 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ168.1, 159.5, 154.3, 136.9, 135.3, 135.2, 130.3, 128.9, 128.4, 127.9,126.6, 125.5, 123.5, 121.9, 120.7, 118.2, 113.5, 70.5.

Example 11-5 Synthesis of2-(3-(Benzyloxy)phenyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound111)

Bright white solid; a reaction time of 4 hours; a yield of 46.6%; amelting point of 93.8 to 95.1° C.; ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s,1H), 7.98 (d, 1H, J=8.4 Hz), 7.76 (t, 1H, J=2.0 Hz), 7.65 (d, 1H, J=8.0Hz), 7.60 (d, 1H, J=8.4 Hz), 7.47 (d, 2H, J=7.2 Hz), 7.42-7.32 (m, 4H),7.13 (dd, 1H, J=2.4, 8.4 Hz), 5.17 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ170.1, 159.5, 153.9, 136.7, 134.5, 134.5, 130.5, 129.0 (q, J=32.6 Hz),128.9, 128.4, 127.8, 124.7 (q, J=270.4 Hz), 122.4, 121.8 (q, J=3.8 Hz),120.8, 120.6 (q, J=3.7 Hz), 118.7, 113.6, 70.5.

Example 11-6 Synthesis of2-(3-(benzyloxy)phenyl)-5-chlorobenzo[d]thiazole (Compound 112)

A reaction time of 22 hours; a yield of 7.4%; ¹H NMR (500 MHz, DMSO-d₆)δ 8.06 (d, 1H, J=2.0 Hz), 7.81 (d, 1H, J=8.5 Hz), 7.75 (br s, 1H), 7.65(d, 1H, J=7.5 Hz), 7.49 (d, 2H, J=7.5 Hz), 7.43-7.36 (m, 5H), 7.13 (dd,1H, J=2.5, 8.5 Hz), 5.18 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.9,159.5, 155.1, 136.8, 134.8, 133.6, 132.5, 130.4, 128.9, 128.4, 127.8,125.9, 123.3, 122.5, 120.7, 118.5, 113.5, 70.5.

Example 12 Synthesis of Compounds 113 to 126

Compounds 113-115, 121, and 125 were synthesized as follows. That is, ina DMF solvent in the presence of Na₂S₂O₅, a solution including Compound107a (0.9-1.4 eq., in the case of Compounds 113 and 114), Compound 107b(0.9-1.4 eq., in the case of Compounds 115 and 125) or Compound 97d(0.9-1.4 eq., in the case of Compound 121) and 3,4-diaminobenzoic acid(1.0 eq., in the case of Compounds 113 and 125), 1,2-phenylenediamine(1.0 eq., in the case of Compounds 114 and 115), or4-chloro-2-aminobenzenethiol (1.0 eq., in the case of Compound 121) washeated to a temperature of 80° C. After DMF was evaporated, water wasadded to the reaction mixture, and a precipitate was filtered, and theresultant product was washed with water and a small amount of methylenechloride and/or ethyl acetate to obtain Compounds 113-115 and 125. Inthe case of Compound 121, DMF was evaporated therefrom, and theresultant solution was extracted with ethyl acetate, and an organiclayer was condensed and the residual was purified twice by silica gelcolumn chromatography using methylene chloride and methanol (10:1) andhexane and ethyl acetate (2:1) to obtain a solid Compound 121.

Synthesis methods of Compounds 116 to 120, 122 to 124, and 126 aredifferent from the method described above, and thus, they are separablydescribed below.

Example 12-1 Synthesis of2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound113)

A reaction time of 6 hours; a yield of 99%; ¹H NMR (500 MHz, DMSO-d₆) δ12.63 (br s, 1H), 8.18 (s, 1H), 8.15 (d, 2H, J=9.5 Hz), 7.84 (d, 1H,J=8.5 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.46 (d, 2H, J=7.0 Hz), 7.38 (t, 2H,J=7.5 Hz), 7.32 (t, 1H, J=7.0 Hz), 7.19 (d, 2H, J=8.5 Hz), 5.17 (s, 2H).

Example 12-2 Synthesis of 2-(4-(benzyloxy)phenyl)-1H-benzo[d]imidazole(Compound 114)

A reaction time of 5.5 hours; a yield of 82.1%; ¹H NMR (400 MHz,DMSO-d₆) δ 8.09 (d, 2H, J=8.8 Hz), 7.52 (m, 2H), 7.44 (d, 1H, J=7.2 Hz),7.37 (t, 1H, J=7.6 Hz), 7.30 (t, 1H, J=7.2 Hz), 7.16-7.12 (m, 4H), 5.15(s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 160.4, 152.0, 144.3, 137.5, 129.1,128.7, 128.6, 128.5, 123.6, 122.4, 119.1 115.9, 70.0.

Example 12-3 Synthesis of 2-(3-(Benzyloxy)phenyl)-1H-benzo[d]imidazole(Compound 115)

A reaction time of 3.3 hours; a yield of 58.2%; ¹H NMR (400 MHz,DMSO-d₆) δ 7.83 (d, 1H, J=1.2 Hz), 7.75 (d, 1H, J=8.0 Hz), 7.64 (d, 1H,J=7.2 Hz), 7.51-7.36 (m, 7H), 7.31 (d, 1H, J=7.2 Hz), 7.17 (t, 1H, J=7.6Hz), 7.10 (d, 1H, J=8.0 Hz), 5.18 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ159.4, 151.7, 114.4, 137.6, 135.6, 132.2, 130.8, 129.1, 128.6, 128.4,123.3, 122.4, 119.7, 119.6, 117.2, 113.1, 112.0, 70.0.

Example 12-4 Synthesis of1-(4-methoxybenzyl)-2-(4-methoxyphenyl)-1H-benzo[d]imidazole (Compound116)

In a methanol (5 mL) solvent in the presence of NH₄Br (362.3 mg, 3.70mmol), a solution including 1,2-phenylenediamine (100 mg, 0.92 mmol) andp-anisaldehyde (0.11 mL, 0.82 mmol) was stirred at room temperature for6 hours, and methanol was evaporated therefrom. The residual wasdistributed between ethyl acetate and water. An organic layer was driedby using MgSO₄, filtered, and evaporated. The residual was purified bysilica gel column chromatography using hexane and ethyl acetate (3:1) toobtain a solid Compound 116.

A reaction time of 6 hours; a yield of 38.0%; ¹H NMR (500 MHz, DMSO-d₆)δ 7.84 (d, 1H, J=8.0 Hz), 7.63 (d, 2H, J=8.5 Hz), 7.27 (m, 1H), 7.18 (m,2H), 6.99 (d, 2H, J=8.5 Hz), 6.94 (d, 2H, J=8.5 Hz), 6.82 (d, 2H, J=9.0Hz), 5.32 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H); ¹³C NMR (100 MHz,DMSO-d₆) δ 161.1, 159.3, 154.3, 143.4, 136.3, 130.9, 128.7, 127.4,122.9, 122.7, 122.7, 119.9, 114.6, 114.4, 110.7, 55.5, 55.5.

Example 12-4 Synthesis of Compounds 117 and 118

In the case of Compound 117 and 118, in a DMF solvent in the presence ofNa₂S₂O₅ (1 eq.), a solution including Compound 97b (1 eq.) and1,2-phenylenediamine was heated at a temperature of 80° C. for 6.5hours. After DMF was evaporated therefrom, the residual was distributedbetween ethyl acetate and water, and the produced precipitate wasfiltered and the resultant product was washed with a hexane and ethylacetate (3:1) co-solvent. The obtained filter cake was dissolved in1,4-dioxane, and 1 N NaOH (1.5 eq.) was added thereto. The reactionmixture was stirred at room temperature for 14 hours, and 1,4-dioxanewas evaporated therefrom. The residual was distributed between ethylacetate and water, an aqueous layer was acidified with 6 N HCl. Theproduced precipitate was filtered with water to obtain Compounds 117 and118:

2-(3-(1H-Benzo[d]imidazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound117)

A reaction time of 6.5 h/14 hours; a yield of 67.7%; ¹H NMR (500 MHz,DMSO-d₆) δ 12.88 (s, 1H), 7.76 (d, 1H, J=7.5 Hz), 7.69 (s, 1H), 7.58 (brs, 2H), 7.43 (t, 1H, J=8.0 Hz), 7.19 (m, 2H), 6.94 (dd, 1H, J=2.5, 8.5Hz), 1.57 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ 175.5, 156.4, 151.5,143.9, 135.8, 132.0, 130.5, 122.8, 120.5, 120.3, 119.4, 117.1, 112.2,79.3, 25.8; and

2-(3-(1H-benzo[d]imidazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound118)

A reaction time of 6.5 hours/14 hours; a yield of 67.7%; ¹H NMR (500MHz, DMSO-d₆) δ 12.88 (s, 1H), 7.76 (d, 1H, J=7.5 Hz), 7.69 (s, 1H),7.58 (br s, 2H), 7.43 (t, 1H, J=8.0 Hz), 7.19 (m, 2H), 6.94 (dd, 1H,J=2.5, 8.5 Hz), 1.57 (s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ 175.5, 156.4,151.5, 143.9, 135.8, 132.0, 130.5, 122.8, 120.5, 120.3, 119.4, 117.1,112.2, 79.3, 25.8.

Example 12-5 Synthesis of2-bromo-4-(5-(trifluoromethyl)-2,3-dihydrobenzo[d]thiazol-2-yl)phenol(Compound 119)

In a DMF (3 mL) solvent, a solution including2-amino-4-trifluoromethylbenzenethiol (100 mg, 0.44 mmol) and3-bromo-4-hydroxybenzaldehyde (88.4 mg, 0.44 mmol) was heated at atemperature of 100° C. for 2.5 hours. After DMF was evaporated, theresidual was distributed between methylene chloride and water, and anorganic layer was evaporated. The produced solid was filtered, andwashed with ethyl acetate to obtain a solid Compound 119.

A reaction time of 2.5 hours; a yield of 10.5%; ¹H NMR (400 MHz,DMSO-d₆) δ 7.64 (d, 1H, J=1.6 Hz), 7.32 (dd, 1H, J=2.0, 8.4 Hz), 7.04(d, 1H, J=7.6 Hz), 6.97 (dd, 1H, J=1.2, 8.4 Hz), 6.95 (d, 1H, J=8.0 Hz),6.76 (s, 1H), 6.58 (s, 1H), 6.38 (d, 1H, J=2.4 Hz), 4.64 (s, 1H); ¹³CNMR (100 MHz, DMSO-d₆) δ 153.5, 146.6, 134.8, 130.8, 128.2 (q, J=31.8Hz), 127.7, 124.5 (q, J=270.1 Hz), 121.4, 117.5 (q, J=3.8 Hz), 116.6,110.6, 105.4 (q, J=3.8 Hz), 69.6.

Example 12-6 Synthesis of2-(3-(benzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid (Compound120)

In a methanol solvent, a solution including Compound 97b (1.0 eq.) and2-aminothiophenol (1.0 eq.) was stirred at room temperature for 22hours. After methanol was evaporated, the residual was purified bysilica gel column chromatography using hexane and ethyl acetate (14:1)as a developer. The obtained product was dissolved with 1,4-dioxane, andthen, 1 N NaOH (1.5 eq.) was added thereto. The reaction mixture wasstirred at room temperature for 17 hours, and 1,4-dioxane wasevaporated. The reaction mixture was stirred at room temperature for 17hours, and 1,4-dioxane was evaporated therefrom. The residual wasdistributed between ethyl acetate and water, an aqueous layer wasacidified with 6 N HCl. The produced precipitate was filtered and washedwith water to obtain Compound 120.

A reaction time of 22 hours/17 hours; a yield of 67.7%; ¹H NMR (400 MHz,DMSO-d₆) δ 13.24 (s, 1H), 8.10 (d, 1H, J=8.0 Hz), 8.02 (d, 1H, J=8.4Hz), 7.64 (d, 1H, J=7.6 Hz), 7.52 (d, 1H, J=1.2 Hz), 7.50 (d, 1H, J=7.2Hz), 7.43 (m, 2H), 7.00 (dd, 1H, J=1.2, 7.6 Hz), 1.54 (s, 6H); ¹³C NMR(100 MHz, DMSO-d₆) δ 175.5, 167.6, 156.6, 154.1, 135.1, 134.6, 131.1,127.4, 126.3, 123.6, 123.0, 122.1, 121.3, 116.7, 79.5, 25.7.

Example 12-7 Synthesis of2-(3-(5-chlorobenzo[d]thiazol-2-yl)phenoxy)-2-methylpropanoic acid(Compound 121)

A reaction time of 7 hours; yield 51.3%; ¹H NMR (400 MHz, DMSO-d₆) δ13.23 (s, 1H), 8.17 (d, 1H, J=8.4 Hz), 8.11 (s, 1H), 7.66 (d, 1H, J=8.0Hz), 7.49 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.03 (d, 1H, J=8.0 Hz), 1.55(s, 6H); ¹³C NMR (100 MHz, DMSO-d₆) δ 175.5, 169.9, 156.7, 155.0, 134.3,133.9, 132.2, 131.2, 126.4, 124.6, 123.0, 122.4, 121.4, 116.9, 79.6,25.7.

Example 12-8 Synthesis of2-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-2-methylpropanoic acid(Compound 122)

1) Synthesis of ethyl 2-(4-formyl-2-methoxyphenoxy)-2-methylpropanoate(Compound 122a)

In a co-solvent including ethanol (3 mL) and DMF (3 mL), IN ethoxysodium (NaOEt) (2.96 mL, 2.96 mmol) was added dropwise to a solutionincluding vanillin (300 mg, 1.97 mmol) and ethyl α-bromoisobutyrate(0.43 mL, 2.93 mmol), and then, the reaction mixture was heated at atemperature of 80° C. overnight. Ethanol was evaporated, and theresidual was distributed between ether and water, and an organic layerwas dried, filtered, and evaporated. The residual was purified by silicagel column chromatography using hexane and ethyl acetate (EtOAc) (4:1)to obtain Compound 122a (188.7 mg, 36%).

Yellow oil; a reaction time: overnight; a yield of 36%; ¹H NMR (400 MHz,CDCl3) δ 9.82 (s, 1H), 7.39 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 6.81 (d,1H, J=8.4 Hz), 4.21 (q, 2H, J=7.2 Hz), 3.87 (s, 3H), 1.64 (s, 6H), 1.20(t, 3H, J=7.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 191.2, 173.8, 151.7,150.8, 131.3, 125.8, 117.5, 110.2, 80.6, 61.8, 56.1, 25.4, 14.3.

2) Synthesis of ethyl2-(4-(benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-2-methylpropanoate(Compound 122b)

In a DMF (3 mL) solvent in the presence of Na₂S₂O₅ (136.1 mg, 0.71mmol), a solution including Compound 122a (188.7 mg, 0.71 mmol) and2-aminothiophenol (0.08 mL, 0.71 mmol) was stirred at room temperaturefor 2 days. After DMF was evaporated, the residual was distributedbetween ethyl acetate and water. An organic layer was dried, filtered,and evaporated. The residual was purified by silica gel columnchromatography using hexane and ethyl acetate (EtOAc) (7:1) to obtainCompound 122b (244.8 mg, 93%).

Yellow oil; a reaction time of 2 days; a yield of 93%; ¹H NMR (400 MHz,CDCl₃) δ8.02 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=7.6 Hz), 7.70 (s, 1H),7.46 (m, 2H), 7.35 (t, 1H, J=6.0 Hz), 6.87 (d, 1H, J=7.2 Hz), 4.24 (q,2H, J=6.4 Hz), 3.95 (s, 3H), 1.63 (s, 6H), 1.25 (t, 3H, J=6.0 Hz); ¹³CNMR (100 MHz, CDCl₃) δ 174.2, 168.0, 154.3, 152.0, 147.6, 135.2, 128.6,126.5, 125.2, 123.2, 121.8, 120.7, 119.6, 110.8, 80.6, 61.7, 56.3, 25.4,14.4

3) Synthesis of2-(4-(Benzo[d]thiazol-2-yl)-2-methoxyphenoxy)-2-methylpropanoic acid(Compound 122b)

Compound 122b (244.8 mg, 0.66 mmol) was dissolved with 1,4-dioxane (2mL), and 1 N NaOH (0.8 mL, 0.8 mmol) was added thereto. The reactioncompound was stirred at room temperature, and the reaction mixture wasdistributed between methylene chloride and water. The reaction compoundwas stirred at room temperature, and the reaction mixture wasdistributed between methylene chloride and water. An aqueous layer wasacidified with 12 N HCl, and extracted with methylene chloride. Anorganic layer was evaporated to obtain Compound 122.

White solid; a reaction time of 6.5 hours; a yield of 58%; ¹H NMR (400MHz, CDCl₃) δ 8.05 (dd, 1H, J=1.2, 8.0 Hz), 7.88 (dd, 1H, J=1.2, 8.8Hz), 7.74 (d, 1H, J=2.0 Hz), 7.54 (dd, 1H, J=2.0, 8.0 Hz), 7.49 (td, 1H,J=1.2, 8.4 Hz), 7.38 (td, 1H, J=1.2, 8.4 Hz), 7.07 (d, 1H, J=8.0 Hz),4.01 (s, 3H), 1.57 (s, 6H).

Example 12-9 Synthesis of 4-(benzo[d]oxazol-2-yl)phenol (Compound 123)

In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0eq.), a solution including 2-aminophenol (1.0 eq.) and4-hydroxybenzaldhehyde (1.0 eq.) was refluxed. After cooling, thereaction mixture was distributed between ethyl acetate and water, and anorganic layer was dried, filtered, and evaporated. The residual waspurified by silica gel column chromatography using hexane and ethylacetate (4:1) to obtain a solid Compound 123.

A reaction time of 4 hours; a yield of 7.6%; ¹H NMR (500 MHz, DMSO-d₆) δ10.34 (s, 1H), 8.03 (d, 2H, J=9.0 Hz), 7.70 (m, 2H), 7.34 (m, 2H), 6.96(d, 2H, J=8.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.4, 161.6, 150.7,142.5, 130.0, 125.4, 125.2, 119.9, 117.8, 116.8, 111.2.

Example 12-10 Synthesis of 2-(4-methoxyphenyl)benzo[d]oxazole (Compound124)

In an acetic acid solvent in the presence of sodium acetate (NaOAc) (3.0eq.), a solution including 2-aminophenol (1.0 eq.) and4-methoxybenzaldhehyde (1.0 eq.) was refluxed. After cooling, thereaction mixture was distributed between ethyl acetate and water, and anorganic layer was dried, filtered, and evaporated. The residual waspurified by silica gel column chromatography using hexane and acetone(25:1) to obtain a solid Compound 124.

A reaction time of 4 hours; a yield of 6.9%; ¹H NMR (400 MHz, DMSO-d₆) δ8.17 (d, 2H, J=9.2 Hz), 7.71 (m, 1H), 7.52 (m, 1H), 7.30 (m, 2H), 6.99(d, 2H, J=9.2 Hz), 3.85 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 163.4,162.5, 150.9, 142.5, 129.6, 124.8, 124.6, 119.8, 114.6, 110.6, 55.6.

Example 12-11 Synthesis of2-(3-(benzyloxy)phenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Compound125)

A reaction time of 5.5 hours; a yield of 42%; ¹H NMR (500 MHz, DMSO-d₆)δ 13.20 (br s, 1H), 7.89 (s, 1H), 7.89-7.86 (m, 2H), 7.82 (d, 1H, J=8.0Hz), 7.68 (br d, 1H, J=6.0 Hz), 7.52-7.48 (m, 3H), 7.42 (t, 2H, J=7.5Hz), 7.35 (t, 1H, J=7.5 Hz), 7.18 (dd, 1H, J=2.0, 8.0 Hz), 5.23 (s, 2H).

Example 12-12 Synthesis of4-(5-chlorobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (Compound 126)

In a DMF (3 mL) solvent in the presence of Na₂S₂O₅ (120.3 mg, 0.63mmol), a solution including 2-amino-4-chlorobenzenethiol (100 mg, 0.63mmol) and syringaldehyde (115.3 mg, 0.63 mmol) was heated at atemperature of 80° C. for 22 hours. After DMF was evaporated, water wasadded thereto. The produced precipitate was filtered, and washed withwater to obtain Compound 126.

A reaction time of 24 hours; a yield of 47.2%; ¹H NMR (400 MHz, DMSO-d₆)δ 9.29 (s, 1H), 8.09 (dd, 1H, J=2.0, 8.4 Hz), 8.04 (br s, 1H), 7.42 (brd, 1H, J=8.4 Hz), 7.27 (s, 1H), 7.27 (s, 1H), 3.86 (s, 3H), 3.86 (s,3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.7, 155.2, 148.9, 140.1, 133.7,131.9, 125.7, 124.2, 123.4, 122.4, 105.5, 56.8.

Example 13 Synthesis of Compounds 127 to 133

Table 8 below is provided to explain substitution patterns of Compounds127 through 133, which are 2-(substitutedphenyl)-5-methyl-1H-benzo[d]imidazole analogs.

TABLE 8 Compound R¹ R² R³ R⁴ 127 H H OH H 128 H OH OH H 129 OH H OH H130 H OMe OH H 131 H H OMe H 132 H OMe OMe H 133 OMe H OMe H

OMe represents a methoxy group, and OEt represents an ethoxy group.

Compounds 127 to 133 were synthesized as follows. In detail, in a DMFsolvent, a solution including benzaldhehyde analogue (1.0 eq.),3,4-diaminotoluene (1.1 eq.), and Na₂S₂O₅ (4.0 eq.) was heated at atemperature of 100° C. for 42 to 47 hours. After DMF was evaporated,water was added thereto, and the produced precipitate was filtered andwashed with water, and a co-solvent including ethyl acetate, methylenechloride, and hexane to obtain Compounds 127 to 133.

Example 13-1 Synthesis of 4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenol(Compound 127)

A reaction time of 42 hours; a yield of 69.0%; ¹H NMR (400 MHz, DMSO-d₆)δ 10.19 (s, 1H), 7.96 (d, 2H, J=8.4 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.36(s, 1H), 7.06 (d, 1H, J=8.0 Hz) 6.92 (d, 2H, J=8.8 Hz), 2.40 (s, 3H);¹³C NMR (100 MHz, DMSO-d₆) δ 160.7, 151.3, 137.3, 135.8, 133.1, 129.3,125.1, 119.2, 116.6, 114.8, 114.3, 21.9.

Example 13-2 Synthesis of4-(5-methyl-1H-benzo[d]imidazol-2-yl)benzene-1,2-diol (Compound 128)

A reaction time of 42 hours; a yield of 15.6%; ¹H NMR (500 MHz, DMSO-d₆)δ 9.41 (s, 1H), 9.20 (s, 1H), 7.57 (s, 1H), 7.42 (d, 1H, J=8.0 Hz), 7.39(d, 1H, J=8.0 Hz), 7.29 (s, 1H), 6.96 (d, 1H, J=8.0 Hz), 6.85 (d, 1H,J=8.0 Hz), 2.40 (s, 3H).

Example 13-3 Synthesis of4-(5-methyl-1H-benzo[d]imidazol-2-yl)benzene-1,3-diol (Compound 129)

A reaction time of 42 hours; a yield of 98.3%; ¹H NMR (500 MHz, DMSO-d₆)δ 10.20 (s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 7.44(s, 1H), 7.14 (d, 1H, J=8.0 Hz), 6.48 (d, 1H, J=8.0 Hz) 6.47 (s, 1H),2.44 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.4, 160.2, 150.9, 135.4,133.6, 129.1, 125.4, 114.5, 114.1, 108.7, 103.8, 103.6, 21.9.

Example 13-4 Synthesis of2-methoxy-4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenol (Compound 130)

A reaction time of 42 hours; a yield of 21.6%; ¹H NMR (400 MHz, DMSO-d₆)δ 12.53 (br s, 1H), 9.49 (s, 1H), 7.67 (s, 1H), 7.54 (d, 1H, J=8.0 Hz),7.38 (d, 1H, J=7.6 Hz), 7.28 (s, 1H), 6.94 (d, 1H, J=8.8 Hz), 6.86 (d,1H, J=8.4 Hz) 3.84 (s, 3H), 2.37 (s, 3H).

Example 13-5 Synthesis of2-(4-methoxyphenyl)-5-methyl-1H-benzo[d]imidazole (Compound 131)

A reaction time of 42 hours; a yield of 43.4%; ¹H NMR (400 MHz, DMSO-d₆)δ 8.08 (d, 2H, J=8.4 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.42 (s, 1H), 7.15 (m,3H), 3.82 (s, 3H), 2.42 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.4,150.5, 136.3, 134.7, 134.0, 129.5, 125.8, 119.6, 115.4, 114.7, 114.3,56.2, 21.9.

Example 13-6 Synthesis of2-(3,4-dimethoxyphenyl)-5-methyl-1H-benzo[d]imidazole (Compound 132)

A reaction time of 42 hours; a yield of 77.1%; ¹H NMR (400 MHz, DMSO-d₆)δ 7.72 (m, 2H), 7.51 (d, 1H, J=8.4 Hz), 7.41 (s, 1H), 7.15 (d, 1H, J=8.8Hz), 7.11 (d, 1H, J=8.0 Hz), 3.85 (s, 3H), 3.82 (s, 3H), 2.41 (s, 3H);¹³C NMR (100 MHz, DMSO-d₆) δ 152.0, 150.7, 149.7, 136.6, 135.0, 133.7,125.6, 120.9, 120.0, 114.8, 114.3, 112.6, 110.6, 56.4, 56.4, 21.9.

Example 13-7 Synthesis of2-(2,4-dimethoxyphenyl)-5-methyl-1H-benzo[d]imidazole (Compound 133)

A reaction time of 47 hours; a yield of 88.7%; ¹H NMR (400 MHz, DMSO-d₆)δ 11.83 (brs, 1H), 8.18 (d, 1H, J=8.8 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.32(s, 1H), 6.93 (d, 1H, J=8.4 Hz), 6.70 (s, 1H), 6.66 (d, 1H, J=8.8 Hz),3.96 (s, 3H), 3.80 (s, 3H), 2.37 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ151.1, 149.7, 146.5, 136.3, 134.7, 133.7, 125.6, 119.9, 118.4, 116.7,115.0, 114.6, 114.2, 21.9.

Example 14 Synthesis of Compounds 134 to 138

Table 9 below is provided to explain substitution patterns of Compounds134 to 138, which are 2-(substitutedphenyl)-5-nitro-1H-benzo[d]imidazole analogs.

TABLE 9 Compound R¹ R² R³ R⁴ 134 H H OH H 135 H OMe OH H 136 H OH OMe H137 H H OMe H 138 H OMe OH OMe

OMe indicates a methoxy group.

Compounds 134 to 138 were synthesized as follows. In detail, in a DMFsolvent, a solution including substituted benzaldhehyde (1.3 eq.),4-nitro-1,2-phenylenediamine (1.0 eq.), and Na₂S₂O₅ (1.1 eq.) was heatedat a temperature of 80° C. After DMF was evaporated, water was addedthereto, and the produced precipitate was filtered, and washed withwater. The filter cake was re-crystallized with methanol to obtainCompounds 134 to 138.

Example 14-1 Synthesis of 4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol(Compound 134)

Yellow solid; a reaction time of 6 hours; a yield of 62.2%; ¹H NMR (500MHz, DMSO-d₆) δ 13.2 (s, 1H), 10.18 (s, 1H), 8.42 (s, 0.5H), 8.25 (s,0.5H), 8.05 (m, 3H), 7.64 (br s, 1H) 6.94 (d, 2H, J=9.0 Hz).

Example 14-2 Synthesis of2-methoxy-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound 135)

Yellow solid; a reaction time of 6 hours; a yield of 23.6%; ¹H NMR (500MHz, DMSO-d₆) δ 13.32 (s, 1H), 9.74 (s, 1H), 8.45 (s, 0.5H), 8.28 (s,0.5H), 8.07 (d, 1H, J=7.0 Hz), 7.76 (s, 1H), 7.70-7.64 (m, 2H), 6.95 (d,1H, J=8.5 Hz), 3.89 (s, 3H).

Example 14-3 Synthesis of2-methoxy-5-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound 136)

Yellow solid; a reaction time of 7.5 hours; a yield of 35.7%; ¹H NMR(500 MHz, DMSO-d₆) δ 13.33 (s, 1H), 9.41 (s, 1H), 8.39 (s, 0.5H), 8.08(s, 0.5H), 8.08 (d, 1H, J=8.0 Hz), 7.64 (m, 3H), 7.11 (d, 1H, J=8.0 Hz),3.85 (s, 3H).

Example 14-4 Synthesis of2-(4-methoxyphenyl)-5-nitro-1H-benzo[d]imidazole (Compound 137)

Yellow solid; a reaction time of 6 hours; a yield of 7.6%; ¹H NMR (500MHz, DMSO-d₆) δ 13.39 (s, 1H), 8.46 (s, 0.5H), 8.28 (s, 0.5H), 8.13 (d,2H, J=8.5 Hz), 8.09 (br d, 1H, J=7.5 Hz), 7.75 (d, 0.5H, J=7.0 Hz), 7.63(d, 0.5H, J=7.5 Hz), 7.12 (d, 2H, J=8.5 Hz), 3.83 (s, 3H).

Example 14-5 Synthesis of2,6-dimethoxy-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (Compound 138)

Yellow solid; a reaction time of 18 hours; a yield of 19.9%; ¹H NMR (500MHz, DMSO-d₆) δ 9.12 (br s, 1H), 8.40 (s, 1H), 8.09 (d, 1H, J=9.0 Hz),7.71 (d, 1H, J=8.5 Hz), 7.52 (s, 2H), 3.88 (s, 6H).

Experimental Example 1 In Vitro ROS Scavenging Activity Assay

1. Preparation of Vascular Endothelial Cells (YPEN-1)

YPEN-1 cells (rat prostatic endothelial cell line) was obtained fromAmerican type culture collection (ATCC, Manassas, Va., USA), and thecells were cultured by using a dulbecco's modified eagle medium (DMEM,Nissui, Tokyo, Japan) containing 2 mM L-glutamine, 100 mg/mlstreptomycin, 2.5 mg/L amphotericin B, and 5% inactivated fetal bovineserum (FBS). Also, the cells were maintained at a temperature of 37° C.in a humid atmosphere-like condition containing 5% CO₂ and 95% air.Also, a medium that did not contain 5% FBS was used as a serum-freemedium (SFM). The cells were sub-cultured in 100 mm plastic flask(Corning Co., New York, USA) every two days to maintain the cell line.

2. ROS Measurement

2′,7′-dichlorodihydrofluorescein diacetate (DCFDA) assay methodaccording to a conventionally known method (Chem Res Toxicol. 5:227-231, 1992) was used. In detail, 12.5 mM DCFDA dissolved in 99.9%ethanol and 600 U/ml esterase dissolved in tertiary distilled water werestored as a stock solution at a temperature of −20° C., and a2′,7′-dichlorodihydrofluorescein (DCFH) solution prepared by mixing 10mM DCFDA and 6 U/ml esterase was cultured at a temperature of 22° C. for20 minutes, and then, refrigerated in a dark place before use. Since theoil-soluble DCFDA was deacetylated into non-fluorescent DCFH due toesterase or oxidative hydrolysis and the DCFH was oxidized due toactivityoxgyen to produce highly-fluorescent 2′,7′-dichlorofluorescein(DCF), the present measurement was performed at an excitation wavelengthof 485 nm and an emission wavelength of 530 nm by using afluorophotometer (GENios, TECAN). Vascular endothelial cells that werepre-treated with 50 μM 3-morpholinosydnonimine hydrochloride (SIN-1) for1 hour were used as a reactive oxygen generation source.

As a result, as shown in FIGS. 1 and 2, Compounds 2, 14, 29, 44, 72, 80,83, 94, 100, 102, 103, 104, 105, and 119 were screened out as a compoundthat has as high scavenging effects on ROS generated by vascularendothelial cells as trolox, which was used as a positive control.

Experimental Example 2 Tyrosinase Inhibitory Effect

Mushroom-derived tyrosinase was sued as an enzyme source in the presentexperiment. Tyrosinase activities were assayed according to aslightly-modified conventionally known method (Life Sci., 1999, 65,241-246). In detail, 20 μl of a mushroom-derived tyrosinase (1000 units)aqueous solution was added to 96-well microplate (Nunc, Denmark) toprepare 200 μl of the total volume of assay mixture containing 1 mML-tyrosin solution and 50 mM phosphate buffer solution (pH 6.5). Theassay mixture was cultured at a temperature of 25° C. for 30 minutes.After the culturing, an amount of the produced DOPA chrome in thereaction mixture was measured by using a microplate reader (HewlettPackard) at 492 nm (OD₄₉₂).

As a result, as shown in FIGS. 3 and 4, Compounds 3, 9, 13, 15, 30, 45,55, 82, 83, 94, 99, and 101 were screened out as a compound that hasbetter tyrosinase inhibitory activities than a kojic acid, which wasused as a positive control.

Experimental Example 3 PPAR Assay

20 μl of a sample and 10 μl of 4× fluormone Pan-PPAR green were spreadonto 384 well plates, and 10 μl of 4×PPAR alpha-LBD/Tb-anti-GST antibodyor 10 μl of 4×PPAR gamma-LBD/Tb-anti-GST antibody were respectively usedin PPARα assay and PPARγ assay. In this regard, a sample compound wasdissolved in such an amount of DMSO that made a final concentration ofthe sample to be 100 μM, and the DMSO final concentration was maintainedwithin 1%. The reaction mixture was left at room temperature for 2 to 6hours, and then, the absorption thereof was measured by using amicroplate reader (Hewlett Packard) at an excitation wavelength of 340nm and at an emission wavelength of 485 nm, and at an exitationwavelength of 340 nm and an emission wavelength of 520 nm to calculate avalue of 520 nm/485 nm. In this regard, if a negative control wasassumed to have an absorption value of 100, a competitive activationrate was defined as follows: 100 minus an absorption value of eachsample. That is, the competitive activation rate indicates a bindingratio of the respective samples with respect to the negative control.

1. PPARα

To evaluate PPARα activities, evaluation values were divided in threescales since the binding activity of fenofibrate, which was used as apositive control, was not high. In detail, a value (3 to 10) that wassimilar to that of the positive control was indicated as ‘≈feno’, avalue (10 to 25) that was slightly higher than that of the positivecontrol was indicated as ‘>feno’, and a value (25 or more) that was muchhigher than that of the positive control was indicated as ‘>>feno’, anda material that has a higher value than a negative control duringmeasurement was designated as ‘ND’. The presence of ND was due to thefluorescence of sample compounds themselves.

As shown in FIGS. 5 and 6, Compounds 13, 16, 17, 20, 24, 25, 26, 28, 31,32, 40, 43, 44, 45, 47, 52, 53, 55, 59, 63, 64, 65, 66, 67, 69, 70, 86,94, 95, 97, 99, 113, 114, and 119 were confirmed as a very excellentPPARα activation agent compared to fenofibrate, which was used as apositive control, and in particular, Compound 26 was confirmed to be themost excellent PPARα activation agent.

2. PPARγ

To evaluate PPARγ a material that has an activity similar to that ofrosiglitazone was indicated as ‘≈Rosi’, and a material that has a higheractivity than that of rosiglitazoneivity was indicated as ‘>Rosi’, andlike PPARα, a material that has a higher value than a negative controlduring measurement was designated as ‘ND’.

As shown in FIGS. 7 and 8, Compounds 13, 16, 17, 20, 24, 25, 26, 28, 31,32, 34, 40, 43, 44, 45, 47, 52, 53, 55, 56, 59, 63, 64, 65, 66, 67, 69,70, 86, 94, 95, 97, 99, 113, and 119 were confirmed as a very excellentPPARγ activation agent compared to rosiglitazone, which was used as apositive control, and in particular, Compound 26 was confirmed to be themost excellent PPARγ activation agent.

In particular, Compound 13, Compound 16, Compound 17, Compound 20,Compound 24, Compound 25, Compound 26, Compound 28, Compound 31,Compound 32, Compound 40, Compound 43, Compound 44, Compound 45,Compound 47, Compound 52, Compound 53, Compound 55, Compound 59,Compound 63, Compound 64, Compound 65, Compound 66, Compound 67,Compound 69, Compound 70, Compound 86, Compound 94, Compound 95,Compound 97, Compound 99, Compound 113, and Compound 119 were identifiedas an activation agent that simultaneously activates PPARα and PPARγ.

Experimental Example 4 Toxicity Test

A suspension of each of Compound 26, Compound 28, Compound 47, Compound67, Compound 86, Compound 94, Compound 97, Compound 99, Compound 113,and Compound 119 in a 0.5% methylcellulose solution was orallyadministered once to a male Balb/c mouse in dosages of 0.5 g/kg, 1 g/kg,and 2 g/kg, and then the survival rate and body weight of the mouse wasrecorded for 7 days.

After the administration, whether the mouse died, clinical symptomsoccurred, and body weight changed were identified and hematologicexamination and blood biochemical examination were performed, andautopsy was performed to identify with naked eyes states of abdominalcavity organs and thoracic cavity organs.

As a result, all the animals neither had distinctive clinical symptomsnor died, and even in consideration of body weight change, hematologicexamination results, blood biochemical examination results, and autopsyreferral, toxicity change was not identified.

As shown in these results, compounds according to the present inventiondid not have the toxicity change in up to 2 g/kg of rats, andaccordingly, it was considered that the compounds were safe in view thata median lethal dose (LD50) thereof for oral administration was 2 g/kgor more.

Hereinafter, preparation examples of a composition including Compound 26according to the present invention will be described in detail. However,the preparation examples are provided for illustrative purpose only anddo not limit the scope of the invention.

Prescription Example 1 Prescription Example of PharmaceuticalComposition Prescription Example 1-1 Preparation of Powder Formulation

20 mg of Compound 26, 100 mg of lactose, and 10 mg of talc were mixedand then a sealing package was filled therewith to prepare a powderformulation.

Prescription Example 1-2 Preparation of Tablet Formulation

20 mg of Compound 26, 100 mg of corn starch, 100 mg of lactose, and 2 mgof magnesium stearate were mixed, and then, the mixture was tabulatedaccording to a conventional tablet preparation method to prepare atablet formulation.

Prescription Example 1-3 Preparation of Capsule Formulation

10 mg of Compound 26, 100 mg of corn starch, 100 mg of lactose, and 2 mgof magnesium stearate were mixed according to a conventional capsulepreparation method, and then, a gelain capsule was filled with themixture to prepare a capsule formulation

Prescription Example 1-4 Preparation of Injection Formulation

10 mg of Compound 26, an appropriate amount of sterilized distilledwater for injection, and an appropriate amount of a pH controller weremixed and then, according to a conventional injection formulationpreparation method, an injection preparation was prepared in such a waythat one ample (2 ml) has the components in the amounts described above.

Prescription Example 1-5 Preparation of Ointment Formulation

10 mg of Compound 26, 250 mg of PEG-4000, 650 mg of PEG-400, 10 mg ofwhite vaseline, 1.44 mg of methyl p-hydroxybenzoate, 0.18 mg of propylp-hydroxybenzoate, and the balanced amount of purified water were mixed,and then, the mixture was used to prepare an ointment formulationaccording to a conventional ointment preparation method.

Prescription Example 2 Prescription Example of Cosmetic CompositionPrescription Example 2-1 Preparation of Nutrition Lotion

3.0 parts by weight of propylene glycol, 0.1 parts by weight ofcarboxypolymer, a trace of a preservative, and the balanced amount ofpurified water were mixed by stirring while heating to a temperature of80 to 85° C. The mixture was loaded into a preparation unit, and then,an emulsifying machine was driven, and 1.0 part by weight of polysolvate60, 0.5 parts by weight of sorbitan sesquiolate, 10.0 parts by weight ofliquid paraffin, 1.0 part by weight of sorbitan stearate, 0.5 parts byweight of lipophilic glyceryl monostearate, 1.5 parts by weight ofstearic acid, 1.0 part by weight of glyceryl stearate/PEG-400 stearate,and 0.2 parts by weight of triethanolamine were heated to a temperatureof 80 to 85° C., and then, loaded thereinto to perform emulsification.When the emulsifying was completely performed, the mixture was stirredby using an agitator while heat-cooling to a temperature of 50° C., andthen, a trace of flavoring agent was added thereto, and after cooling toa temperature of 45° C., a trace of pigment was added thereto, andCompound 26 was added thereto at a temperature of 35° C. and theresultant mixture was cooled to a temperature of 25° C. and aged.

Prescription Example 2-2 Preparation of Nutrition Cream

0.3 parts by weight of carboxypolymer, 5.0 parts by weight of butyleneglycol, 3.0 parts by weight of glycerin, and the balanced amount ofpurified water were mixed by stirring while heating to a temperature of80 to 85° C., and the mixture was loaded into a preparation unit, andthen, an emulsifying machine was driven. Then, 2.0 parts by weight of astearic acid, 2.0 parts by weight of cetylalcohol, 2.0 parts by weightof glyceryl monostearate, 0.5 parts by weight ofpolyoxyethylenesorbitanmonostearate, 0.5 parts by weight ofsorbitansesquiolate, 1.0 part by weight of wax, 1.0 part by weight ofglyceryl monostearate/glyceryl stearate/polyoxyethylene stearate, 4.0parts by weight of liquid paraffin, 4.0 parts by weight of squalane, and4.0 parts by weight of caprylic/capric triglyceride were heated to attemperature of 80 to 85° C. and then loaded thereinto, and then, 0.5parts by weight of triethanolamine was loaded thereinto and emulsifyingwas performed thereon. When the emulsifying was completely performed,the resultant mixture was stirred by using an agitator while cooling toa temperature of 35° C., and then, Compound 26 was loaded thereinto andcooled to a temperature of 25° C. and aged.

Prescription Example 2-3 Preparation of Washfoam

30.0 parts by weight of TEA-cocoyl glutamate, 10.0 parts by weight ofdisodium laureth sulfosuccinateglycerin, 10.0 parts by weight ofglycerin, 2.0 parts by weight of cocamide DEA, 1.0 part by weight ofPEG-120 methylglucose dioliate, 0.5 parts by weight of methylgluceth-20, 0.5 parts by weight of PEG-150 pentaerythrityl tetrastearate, 0.05 parts by weight of tetrasodium EDTA, and a trace ofpreservative were sequentially added into a preparation unit, and then,heated to a temperature of 60 to 65° C. and then stirred for 15 minutes.When the stirring was completely performed, some of purified water wasadded therein and then the resultant mixture was stirred for 30 minutes,and then, some of purified water was slowly added thereinto and then theresultant mixture was stirred for 30 minutes, and then cooled to atemperature of 35° C., and Compound 26 and a flavoring agent were addedthereinto, and then, the resultant mixture was cooled to a temperatureof 25° C. and aged.

Prescription Example 3 Supplementary Health Food Prescription Example3-1 Preparation of Health Foods

1 mg of Compound 26, an appropriate amount of vitamin mixture (including70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B 1,0.15 mg of vitamin B 2, 0.5 mg of vitamin B 6, 0.2 μg of vitamin B 12,10 mg of vitamin C, 10 μg of biotin, 1.7 mg of nicotinamide, 50 μg offolate, and 0.5 mg of calcium pantothenate), and an appropriate amountof mineral mixture (1.75 mg of ferrous sulphate, 0.82 mg of zinc oxide,25.3 mg of magnesium carbonate, 15 mg of potassium phosphate monobasic,55 mg of calcium phosphate dibasic, 90 mg of potassium citrate, 100 mgof calcium carbonate, and 24.8 mg of magnesium chloride) were mixed, andthen, prepared in a granule formulation, and then, a health food wasprepared according to a conventional method.

Prescription Example 3-2 Preparation of Health Beverages

1 mg of Compound 26, 1000 mg of a citric acid, 100 g of oligosaccharide,2 g of plum concentrate, 1 g of taurine, and such an amount of purifiedwater that a total volume of the mixture reached 900 ml were prepared,and these components were mixed according to a conventional healthbeverage preparation method, and then, the mixture was stirred for about1 hour while heating at a temperature of 85° C., and then the preparedsolution was filtered, and a sterilized 2 L container was filledtherewith and then, sealed and sterilized, and then, refrigerated.

What is claimed is:
 1. A skin-whitening method, comprising:administering to a subject a compound of Formula I,

wherein R¹ to R⁴ are identical to or different from each other, and areany one of H, OH, a C₁ to C₄ alkoxy, and bromine, wherein X is any oneof H, Cl, and CF₃.
 2. The skin-whitening method of claim 1, wherein thecompound is selected from the group consisting of4-(benzo[d]thiazol-2-yl)phenol] (Compound 13),4-(benzo[d]thiazol-2-yl)benzene-1,2-diol (Compound 14),4-(benzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 15),4-(benzo[d]thiazol-2-yl)-2-methoxyphenol (Compound 16),4-(benzo[d]thiazol-2-yl)-2-ethoxyphenol (Compound 17),2-(3,4-dimethoxyphenyl)benzo[d]thiazol (Compound 20),4-(benzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (Compound 25), and4-(benzo[d]thiazol-2-yl)-2-bromophenol (Compound 26).
 3. Theskin-whitening method of claim 2, wherein the compound is administeredto the subject in a range of 0.001 to 100 mg/kg daily.
 4. Theskin-whitening method of claim 1, wherein the compound is selected fromthe group consisting of4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound 28),4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,2-diol (Compound29), 4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)benzene-1,3-diol(Compound 30),2-methoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol (Compound31), 2-ethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 32), 2-(4-methoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol(Compound 34),2-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)benzo[d]thiazol (Compound37), and 2,6-dimethoxy-4-(5-(trifluoromethyl)benzo[d]thiazol-2-yl)phenol(Compound 40).
 5. The skin-whitening method of claim 4, wherein thecompound is administered to the subject in a range of 0.001 to 100 mg/kgdaily.
 6. The skin-whitening method of claim 1, wherein the compound isselected from the group consisting of4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 82),4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,2-diol (Compound 83),4-(5-chlorobenzo[d]thiazol-2-yl)benzene-1,3-diol (Compound 84),4-(5-chlorobenzo[d]thiazol-2-yl)-2-ethoxyphenol (Compound 86),2-bromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 95),2,6-dibromo-4-(5-chlorobenzo[d]thiazol-2-yl)phenol (Compound 96), and4-(5-chlorobenzo[d]thiazol-2-yl)-2,6-dimethoxyphenol (Compound 126). 7.The skin-whitening method of claim 4, wherein the compound isadministered to the subject in a range of 0.001 to 100 mg/kg daily.